Is CD96 p.Ala457= (c.1371A>G) pathogenic?

CD96 p.Ala457= (c.1371A>G) is classified Benign in CD96 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.53%, nfe).

How common is CD96 p.Ala457= (c.1371A>G) in the general population?

CD96 p.Ala457= (c.1371A>G) is low-frequency (popmax 3.53%, nfe) (gnomAD).

CD96 p.Ala457=

c.1371A>G · rs34636484 · VCV1619538

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.53%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.39
Overall
CADD	3.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.53% European (non-Finnish) · 40,202/1,140,038 alleles

Filtering AF 3.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.49%

Overall 2.88% 45,255/1,570,406 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.37%	19
European (non-Finnish)grpmax	3.53%	28
Remaining individualsnot grpmax-eligible	2.43%	41
Ashkenazi Jewishnot grpmax-eligible	2.35%	43
Finnishnot grpmax-eligible	2.2%	46
Admixed American	1.39%	72
Middle Eastern	1.13%	88
African / African-American	0.541%	185
South Asian	0.137%	727

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala457=
Coding: c.1371A>G
MANE Select: NM_005816
dbSNP: rs34636484
Type: single nucleotide variant
Location: chr3:111637245 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 457: the 'disordered' region

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

Similar variants

CD96 p.Ala457Val Uncertain significance ★ ⚠ same residue
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

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-ala457 (accessed [today's date]).

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