Is CD96 p.Ala142Pro (c.424G>C) pathogenic?

CD96 p.Ala142Pro (c.424G>C) is classified Benign in CD96 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0644); Common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD96 p.Ala142Pro (c.424G>C)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

CD96 p.Ala142Pro

Q: How common is CD96 p.Ala142Pro (c.424G>C) in the general population?

CD96 p.Ala142Pro (c.424G>C) is common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.424G>C · rs2276872 · VCV1538658

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.4%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.29	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 1.3	GERP -0.24, phastCons 0.035
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	8.702	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 15.4% East Asian · 6,886/44,788 alleles

Filtering AF 15.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.9%

Overall 1.62% 26,038/1,605,728 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	15.4%	7
Admixed American	10.9%	9
African / African-American	5.47%	18
Remaining individualsnot grpmax-eligible	1.98%	50
South Asian	1.62%	62
Middle Eastern	0.612%	163
European (non-Finnish)	0.481%	208
Ashkenazi Jewishnot grpmax-eligible	0.318%	314
Finnishnot grpmax-eligible	0.0313%	3,192

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: CD96
Protein: p.Ala142Pro
Coding: c.424G>C
MANE Select: NM_005816
dbSNP: rs2276872
Type: single nucleotide variant
Location: chr3:111567528 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 142: a UniProt-annotated variant site (in)

Full CD96 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD96 c.1249+1G>A Uncertain significance ★★ same type
CD96 c.544-1512C>T Uncertain significance ★★ ⚠ same type
CD96 p.Asp205Gly Uncertain significance ★★ ⚠ same type
CD96 p.Asp224Asn Uncertain significance ★★ ⚠ same type
CD96 p.Ile151Thr Uncertain significance ★★ ⚠ same type
CD96 p.Leu120Pro Uncertain significance ★★ ⚠ same type
CD96 p.Lys500Arg Uncertain significance ★★ ⚠ same type
CD96 p.Pro346Ser 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/cd96-p-ala142pro (accessed [today's date]).

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