Is CA5B p.Ala135Pro (c.403G>C) pathogenic?

CA5B p.Ala135Pro (c.403G>C) is classified Uncertain significance in CA5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8403); Very rare (popmax 0.00175%, afr).

How common is CA5B p.Ala135Pro (c.403G>C) in the general population?

CA5B p.Ala135Pro (c.403G>C) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about CA5B p.Ala135Pro (c.403G>C)?

AlphaMissense predicts likely pathogenic (score 0.8403) — an in-silico prediction, not a clinical call.

CA5B p.Ala135Pro

c.403G>C · VCV3994226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8403	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -8.68	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 18 kb · p 0.53 · regional, not allelic
Overall
CADD	27.1	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 0.00175% African / African-American · 1/57,006 alleles

Filtering AF 0.000242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00058% 7/1,206,177 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,006
European (non-Finnish)	0.000672%	148,744

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: CA5B
Protein: p.Ala135Pro
Coding: c.403G>C
MANE Select: NM_007220
Type: single nucleotide variant
Location: chrX:15772558 (GRCh38)
Structure: AlphaFold pLDDT 83.33
Residue 135: the alpha-carbonic anhydrase domain

Full CA5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA5B p.Ala138Val Uncertain significance ★ ⚠ same type
CA5B p.Ala170Glu Uncertain significance ★ ⚠ same type
CA5B p.Ala47Val Uncertain significance ★ ⚠ same type
CA5B p.Arg282Cys Uncertain significance ★ ⚠ same type
CA5B p.Arg282His Uncertain significance ★ ⚠ same type
CA5B p.Arg290Leu Uncertain significance ★ ⚠ same type
CA5B p.Arg293His Uncertain significance ★ ⚠ same type
CA5B p.Arg32Ser 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/ca5b-p-ala135pro (accessed [today's date]).

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