Is CD96 p.Leu120Pro (c.359T>C) pathogenic?

CD96 p.Leu120Pro (c.359T>C) is classified Uncertain significance in CD96 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.7641); Ultra-rare (popmax 0.0297%, nfe).

How common is CD96 p.Leu120Pro (c.359T>C) in the general population?

CD96 p.Leu120Pro (c.359T>C) is ultra-rare (popmax 0.0297%, nfe) (gnomAD).

What do computational predictors say about CD96 p.Leu120Pro (c.359T>C)?

AlphaMissense predicts likely pathogenic (score 0.7641) — an in-silico prediction, not a clinical call.

CD96 p.Leu120Pro

c.359T>C · rs199773662 · VCV1448107

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7641	likely pathogenic · top 5% in CD96
REVEL	0.184	benign-leaning
SaProt	LLR -9.73	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 108 kb · p 0.013 · regional, not allelic
Overall
CADD	23.9	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 0.0297% European (non-Finnish) · 351/1,179,898 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0242% 391/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,125
European (non-Finnish)grpmax	0.0297%	3,362
Admixed American	0.0283%	3,531
Middle Eastern	0.0165%	6,062
African / African-American	0.00266%	37,535

Remaining individuals 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.Leu120Pro
Coding: c.359T>C
MANE Select: NM_005816
dbSNP: rs199773662
Type: single nucleotide variant
Location: chr3:111545343 (GRCh38)
Gene constraint: LOEUF 1.16 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB
Residue 120: a β-strand; the ig-like v-type 1 domain

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.Lys500Arg Uncertain significance ★★ ⚠ same type
CD96 p.Pro346Ser Uncertain significance ★★ ⚠ same type
CD96 p.Ser474Leu 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-leu120pro (accessed [today's date]).

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