Is ABCA4 p.Val552Ile (c.1654G>A) pathogenic?

ABCA4 p.Val552Ile (c.1654G>A) is classified Likely benign in ABCA4 (ClinVar, Expert panel, 9 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.0885); Rare (popmax 0.458%, nfe); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Val552Ile (c.1654G>A)?

ABCA4 p.Val552Ile (c.1654G>A) is associated with ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Val552Ile (c.1654G>A) in the general population?

ABCA4 p.Val552Ile (c.1654G>A) is rare (popmax 0.458%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Val552Ile (c.1654G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

ABCA4 p.Val552Ile

c.1654G>A · rs145525174 · VCV193990

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.458%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

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

PP3 BS3_Supporting BS1_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000350.3(ABCA4):c.1654G>A variant in ABCA4 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 552; p.Val552Ile. The GroupMax filtering allele frequency in gnomAD v4.1.0 is 0.004481, which is greater than the ClinGen ABCA4 VCEP’s threshold for BS1_Supporting (>0.00163). The computational predictor REVEL gives a score of 0.685 which is in the range of 0.644-0.772 meeting PP3. ABCA4 expression and ATPase activity in HEK293 cells showed expression close to WT levels and only a modest reduction in ATPase activity, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 29847635). In summary, this variant meets the criteria to be classified as likely benign for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): BS1_Supporting, BS3_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -6.91	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	19.56	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 0.458% European (non-Finnish) · 5,409/1,179,984 alleles

Filtering AF 0.448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.444%

Overall 0.371% 5,986/1,614,084 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.458%	218
Finnishnot grpmax-eligible	0.234%	427
Remaining individualsnot grpmax-eligible	0.226%	443
South Asian	0.214%	467
Middle Eastern	0.149%	673
African / African-American	0.06%	1,667
Admixed American	0.055%	1,819
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
East Asian	0.00223%	44,876

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.Val552Ile
Coding: c.1654G>A
MANE Select: NM_000350
dbSNP: rs145525174
Type: single nucleotide variant
Location: chr1:94063218 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 552: 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); a UniProt-annotated variant site (in rp19; benign; no effect on n-all-trans-retinylidenephosphatidylethanolamine binding; does not affect solubility; does not affect intracellular vesicle localization; does not affect basal and n-ret-pe-stimulated atpase activity); a β-strand

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

Disease context

Also linked: severe early-childhood-onset retinal dystrophy inherited retinal dystrophy

Similar variants

ABCA4 p.Val552Ala Uncertain significance ★★ ⚠ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3328+2T>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

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-val552ile (accessed [today's date]).

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