Is CA4 p.Val264Met (c.790G>A) pathogenic?

CA4 p.Val264Met (c.790G>A) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1494); Very rare (popmax 0.00458%, nfe).

How common is CA4 p.Val264Met (c.790G>A) in the general population?

CA4 p.Val264Met (c.790G>A) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about CA4 p.Val264Met (c.790G>A)?

AlphaMissense predicts likely benign (score 0.1494) — an in-silico prediction, not a clinical call.

CA4 p.Val264Met

c.790G>A · rs748492425 · VCV967541

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1494	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -7.76	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 -3.8	GERP -2.2
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	0.02	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 0.00458% European (non-Finnish) · 54/1,178,122 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00322%

Overall 0.0036% 58/1,609,980 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,817
Admixed American	0.00336%	29,742
Remaining individualsnot grpmax-eligible	0.00161%	62,300
Finnishnot grpmax-eligible	0.00157%	63,630

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.Val264Met
Coding: c.790G>A
MANE Select: NM_000717
dbSNP: rs748492425
Type: single nucleotide variant
Location: chr17:60159275 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 264: the alpha-carbonic anhydrase domain; a β-strand

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

Similar variants

CA4 p.Val264= 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.Arg279Pro Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His Uncertain significance ★★ ⚠ same type
CA4 p.Arg50Ser Uncertain significance ★★ ⚠ same type
CA4 p.Asp131Asn 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-val264met (accessed [today's date]).

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