Is CA2 p.Val142Ile (c.424G>A) pathogenic?

CA2 p.Val142Ile (c.424G>A) is classified Uncertain significance in CA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-28). AlphaMissense: likely benign (0.2881); Ultra-rare (popmax 0.0164%, mid).

How common is CA2 p.Val142Ile (c.424G>A) in the general population?

CA2 p.Val142Ile (c.424G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CA2 p.Val142Ile (c.424G>A)?

AlphaMissense predicts likely benign (score 0.2881) — an in-silico prediction, not a clinical call.

CA2 p.Val142Ile

c.424G>A · rs373116402 · VCV1354540

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2881 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2881	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -11.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,424 bp · p 0.35 · regional, not allelic
Overall
CADD	25.8	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00359% 58/1,613,368 alleles · ultra-rare exomes 52/1,461,224 · genomes 6/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
East Asian	0.0111%	8,975
African / African-American	0.00801%	12,486
Remaining individualsnot grpmax-eligible	0.00801%	12,492
South Asian	0.00769%	13,010
European (non-Finnish)	0.00288%	34,690

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: CA2
Protein: p.Val142Ile
Coding: c.424G>A
MANE Select: NM_000067
dbSNP: rs373116402
Type: single nucleotide variant
Location: chr8:85474396 (GRCh38)
Gene constraint: LOEUF 1.491 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.38 · 1249 PDB
Residue 142: the alpha-carbonic anhydrase domain; a β-strand

Full CA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA2 c.232+1G>A Pathogenic ★★ same type
CA2 p.Gln92Pro Likely pathogenic ★★ same type
CA2 p.Glu204Ter Pathogenic/Likely pathogenic ★★ same type
CA2 p.Tyr193Ter Likely pathogenic ★★ same type
CA2 p.Arg181Cys Uncertain significance ★★ ⚠ same type
CA2 p.Arg181His Uncertain significance ★★ ⚠ same type
CA2 p.Arg226His Uncertain significance ★★ ⚠ same type
CA2 p.Arg245Cys 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/ca2-p-val142ile (accessed [today's date]).

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