Is ABCA4 p.Arg226Ser (c.676C>A) pathogenic?

ABCA4 p.Arg226Ser (c.676C>A) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-08-06). AlphaMissense: likely benign (0.2328); Very rare (popmax 0.00322%, nfe); Associated with severe early-childhood-onset retinal dystrophy.

What condition is associated with ABCA4 p.Arg226Ser (c.676C>A)?

ABCA4 p.Arg226Ser (c.676C>A) is associated with severe early-childhood-onset retinal dystrophy, age related macular degeneration 2, retinitis pigmentosa 19 (ClinVar).

How common is ABCA4 p.Arg226Ser (c.676C>A) in the general population?

ABCA4 p.Arg226Ser (c.676C>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

How is Severe early-childhood-onset retinal dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA4 p.Arg226Ser (c.676C>A)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg226Ser

c.676C>A · rs149780335 · VCV930839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe early-childhood-onset retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.522	indeterminate
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.80	donor gain · deltas
Pangolin	Δ0.58	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.4	GERP -0.23, phastCons 0.48
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	24.4	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 0.00322% European (non-Finnish) · 38/1,180,002 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,613,900 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,053
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg226Ser
Coding: c.676C>A
MANE Select: NM_000350
dbSNP: rs149780335
Type: single nucleotide variant
Location: chr1:94098886 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 226: 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 disulfide bond

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

Disease context

severe early-childhood-onset retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 2 retinitis pigmentosa 19 cone-rod dystrophy 3

For Severe early-childhood-onset retinal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ABCA4 p.Arg226Cys Uncertain significance ★★ ⚠ same residue
ABCA4 p.Arg226His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA4 p.Arg226Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg226ser (accessed [today's date]).

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