Is ABCA4 p.Arg212His (c.635G>A) pathogenic?

ABCA4 p.Arg212His (c.635G>A) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0778); Common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with ABCA4 p.Arg212His (c.635G>A)?

ABCA4 p.Arg212His (c.635G>A) is associated with inherited retinal dystrophy (ClinVar).

What do computational predictors say about ABCA4 p.Arg212His (c.635G>A)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

ABCA4 p.Arg212His

Q: How common is ABCA4 p.Arg212His (c.635G>A) in the general population?

ABCA4 p.Arg212His (c.635G>A) is common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.635G>A · rs6657239 · VCV99454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -6.05	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 1.1	GERP -0.55, phastCons 0.56
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	22.0	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 6.95% African / African-American · 5,215/75,014 alleles

Filtering AF 6.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.73%

Overall 3.97% 64,113/1,613,470 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.95%	14
East Asian	6.12%	16
Finnishnot grpmax-eligible	5.96%	17
Remaining individualsnot grpmax-eligible	4.33%	23
Admixed American	4.24%	24
European (non-Finnish)	3.72%	27
Middle Eastern	3.55%	28
Amishnot grpmax-eligible	3.4%	29
Ashkenazi Jewishnot grpmax-eligible	3.17%	32
South Asian	2.28%	44

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.Arg212His
Coding: c.635G>A
MANE Select: NM_000350
dbSNP: rs6657239
Type: single nucleotide variant
Location: chr1:94098927 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 212: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (in stgd1 and cord3; likely pathogenic; common mutation in southern europe); a UniProt-annotated variant site (in); an α-helix; a disulfide bond

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 p.Arg212Cys Pathogenic ★★★ ⚠ same residue
ABCA4 p.Arg212Ser Uncertain significance ★ same residue
ABCA4 c.1937+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>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-arg212his (accessed [today's date]).

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