Is CA4 p.Ala308Asp (c.923C>A) pathogenic?

CA4 p.Ala308Asp (c.923C>A) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-22). AlphaMissense: ambiguous (0.3454); Rare (popmax 0.125%, eas).

How common is CA4 p.Ala308Asp (c.923C>A) in the general population?

CA4 p.Ala308Asp (c.923C>A) is rare (popmax 0.125%, eas) (gnomAD).

What do computational predictors say about CA4 p.Ala308Asp (c.923C>A)?

AlphaMissense predicts ambiguous (score 0.3454) — an in-silico prediction, not a clinical call.

CA4 p.Ala308Asp

c.923C>A · rs201580764 · VCV426912

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3454 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, eas)

Computational evidence

Protein change
AlphaMissense	0.3454	ambiguous
REVEL	0.337	indeterminate
SaProt	LLR -7.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP 0.2, phastCons 0.072
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	17.41	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 0.125% East Asian · 56/44,864 alleles

Filtering AF 0.0986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00645% 104/1,612,022 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.125%	801
Remaining individualsnot grpmax-eligible	0.0241%	4,158
African / African-American	0.0227%	4,413
South Asian	0.0176%	5,687

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.Ala308Asp
Coding: c.923C>A
MANE Select: NM_000717
dbSNP: rs201580764
Type: single nucleotide variant
Location: chr17:60159408 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB

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

Similar variants

CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same residue
CA4 p.Ala308= Likely benign ★ same residue
CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val 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-ala308asp (accessed [today's date]).

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