Is CA4 p.Arg279His (c.836G>A) pathogenic?

CA4 p.Arg279His (c.836G>A) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.7175); Ultra-rare (popmax 0.0374%, afr).

How common is CA4 p.Arg279His (c.836G>A) in the general population?

CA4 p.Arg279His (c.836G>A) is ultra-rare (popmax 0.0374%, afr) (gnomAD).

What do computational predictors say about CA4 p.Arg279His (c.836G>A)?

AlphaMissense predicts likely pathogenic (score 0.7175) — an in-silico prediction, not a clinical call.

CA4 p.Arg279His

c.836G>A · rs372344598 · VCV1510253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7175	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	25.3	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 0.0374% African / African-American · 28/74,928 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00261% 42/1,609,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0374%	2,676
Remaining individualsnot grpmax-eligible	0.0016%	62,310
South Asian	0.00111%	90,454
European (non-Finnish)	0.00102%	98,168

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.Arg279His
Coding: c.836G>A
MANE Select: NM_000717
dbSNP: rs372344598
Type: single nucleotide variant
Location: chr17:60159321 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 279: the alpha-carbonic anhydrase domain

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA4 p.Arg279Pro Uncertain significance ★★ ⚠ same residue
CA4 p.Arg279Cys Uncertain significance ★ ⚠ same residue
CA4 p.Arg279Leu Uncertain significance ★ ⚠ same residue
CA4 p.Arg279= Likely benign ★ same residue
CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val Uncertain significance ★★ ⚠ same type
CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His Uncertain significance ★★ ⚠ same type

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-arg279his (accessed [today's date]).

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