Is ABCA4 p.Ser2255Ile (c.6764G>T) pathogenic?

ABCA4 p.Ser2255Ile (c.6764G>T) is classified Benign in ABCA4 (ClinVar, Expert panel, 14 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.0661); Common (popmax 48.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Ser2255Ile (c.6764G>T)?

ABCA4 p.Ser2255Ile (c.6764G>T) is associated with ABCA4-related retinopathy, age related macular degeneration 2, severe early-childhood-onset retinal dystrophy (ClinVar).

What do computational predictors say about ABCA4 p.Ser2255Ile (c.6764G>T)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

ABCA4 p.Ser2255Ile

Q: How common is ABCA4 p.Ser2255Ile (c.6764G>T) in the general population?

ABCA4 p.Ser2255Ile (c.6764G>T) is common (popmax 48.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6764G>T · rs6666652 · VCV99494

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 48.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

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

BP4 BA1

Curation rationale (ClinGen, verbatim)

The NM_000350.3(ABCA4):c.6764G>T variant in ABCA4 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 2255 (p.Ser2255Ile). The GroupMax filtering allele frequency in gnomAD v4.1.0 is 0.4845, which is greater than the ClinGen ABCA4 VCEP’s threshold for BA1 (>0.163). The computational predictor REVEL gives a score of 0.2 which is in the range of 0.184-0.290, and the variant has a SpliceAI donor gain score of 0.01, which is below the 0.1 cutoff meeting BP4. In summary, this variant meets the criteria to be classified as benign for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): BA1, BP4.

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

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.068	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	1.718	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 48.9% African / African-American · 36,625/74,942 alleles

Filtering AF 48.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 48.3%

Overall 6.19% 99,875/1,613,784 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	48.9%	2
Middle Eastern	12.7%	8
Amishnot grpmax-eligible	9.43%	11
Remaining individualsnot grpmax-eligible	7.58%	13
Admixed American	7.25%	14
Ashkenazi Jewishnot grpmax-eligible	6.92%	14
South Asian	5.08%	20
European (non-Finnish)	3.83%	26
East Asian	2.29%	44
Finnishnot grpmax-eligible	0.654%	153

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.Ser2255Ile
Coding: c.6764G>T
MANE Select: NM_000350
dbSNP: rs6666652
Type: single nucleotide variant
Location: chr1:93996161 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2255: 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 (found in a patient with macular dystrophy; uncertain significance); a UniProt-annotated variant site (in stgd1 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance; also found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (in)

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 retinitis pigmentosa 19 cone-rod dystrophy 3 inherited retinal dystrophy

Similar variants

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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>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-ser2255ile (accessed [today's date]).

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