Is CA4 p.Arg69His (c.206G>A) pathogenic?

CA4 p.Arg69His (c.206G>A) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.0904); Ultra-rare (popmax 0.0187%, sas); Associated with inherited retinal dystrophy.

What condition is associated with CA4 p.Arg69His (c.206G>A)?

CA4 p.Arg69His (c.206G>A) is associated with inherited retinal dystrophy, retinitis pigmentosa 17 (ClinVar).

How common is CA4 p.Arg69His (c.206G>A) in the general population?

CA4 p.Arg69His (c.206G>A) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about CA4 p.Arg69His (c.206G>A)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

CA4 p.Arg69His

c.206G>A · rs121434552 · VCV17609

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.8	GERP -4
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	0.003	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 0.0187% South Asian · 17/91,084 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00204% 33/1,613,990 alleles · ultra-rare exomes 33/1,461,678 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0048%	20,834
East Asian	0.00446%	22,436
European (non-Finnish)	0.000593%	168,550

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: CA4
Protein: p.Arg69His
Coding: c.206G>A
MANE Select: NM_000717
dbSNP: rs121434552
Type: single nucleotide variant
Location: chr17:60156653 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 69: a UniProt-annotated variant site (in rp17; has no effect on carbonate dehydratase activity; loss of interaction with slc4a4); the alpha-carbonic anhydrase domain

Full CA4 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

Also linked: retinitis pigmentosa 17

Similar variants

CA4 p.Arg69Cys Uncertain significance ★ ⚠ same residue
CA4 p.Arg69Ser Uncertain significance ★ ⚠ same residue
CA4 p.Asp268Asn Uncertain significance ★★ ⚠ same condition
CA4 p.Gly87Glu Uncertain significance ★★ ⚠ same condition
CA4 p.Pro227Leu Uncertain significance ★★ ⚠ same condition
CA4 p.Ala164= Benign/Likely benign ★★ same condition
CA4 p.Asn177Lys Benign/Likely benign ★★ ⚠ same condition
CA4 p.Asp161= Likely benign ★★ 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/ca4-p-arg69his (accessed [today's date]).

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