Is ABCA4 p.Val675Ile (c.2023G>A) pathogenic?

ABCA4 p.Val675Ile (c.2023G>A) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.162); Ultra-rare (popmax 0.0333%, amr); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Val675Ile (c.2023G>A)?

ABCA4 p.Val675Ile (c.2023G>A) is associated with ABCA4-related disorder, age related macular degeneration 2, severe early-childhood-onset retinal dystrophy (ClinVar).

How common is ABCA4 p.Val675Ile (c.2023G>A) in the general population?

ABCA4 p.Val675Ile (c.2023G>A) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

What do computational predictors say about ABCA4 p.Val675Ile (c.2023G>A)?

AlphaMissense predicts likely benign (score 0.162) — an in-silico prediction, not a clinical call.

ABCA4 p.Val675Ile

c.2023G>A · rs575453437 · VCV288341

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

ClinGen expert panel — ABCA4 VCEP

Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):

PM2_Supporting PS4 PM3_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_000350.3(ABCA4):c.2023G>A is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 675; p.Val675Ile. The total minor allele frequency in gnomAD v4.1.0 is 0.00003098 (50/1614116 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.705 which is in the range of 0.644-0.772 meeting PP3. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 29.8 and CI of 10.93 to 93.94, which is above the ABCA4 VCEP threshold of ≥5 where the CI does not contain 1 (PS4; PMID: 35120629).This variant has been detected in well over five individuals with ABCA4-related retinopathy who were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PM3_Strong, 2.25 pts; PMIDs: 23499370, 28041643, 41642025, 39643591). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0): PS4, PM3_Strong, PP3, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.162	likely benign ⚠ discordant with ClinVar
REVEL	0.705	pathogenic-leaning
SaProt	LLR -10.52	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.97, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,008 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0031% 50/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
Middle Eastern	0.0165%	6,062
South Asian	0.011%	9,106
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,510
Finnishnot grpmax-eligible	0.00156%	64,036
African / African-American	0.00133%	75,028
European (non-Finnish)	0.00127%	78,668

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA4
Protein: p.Val675Ile
Coding: c.2023G>A
MANE Select: NM_000350
dbSNP: rs575453437
Type: single nucleotide variant
Location: chr1:94060674 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 675: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); an α-helix; a disulfide bond

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: age related macular degeneration 2 severe early-childhood-onset retinal dystrophy Stargardt disease 3 retinitis pigmentosa 19 cone-rod dystrophy 3

Similar variants

ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4254-1G>C Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A Pathogenic ★★★ same condition
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5018+2T>C Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca4-p-val675ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown