Is CD99L2 p.Val181Ala (c.542T>C) pathogenic?

CD99L2 p.Val181Ala (c.542T>C) is classified Uncertain significance in CD99L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.0885); Ultra-rare (popmax 0.0333%, afr).

How common is CD99L2 p.Val181Ala (c.542T>C) in the general population?

CD99L2 p.Val181Ala (c.542T>C) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about CD99L2 p.Val181Ala (c.542T>C)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

CD99L2 p.Val181Ala

c.542T>C · VCV3488242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -4.55	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 7.3	GERP 0.91, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 130 kb · p 0.025 · regional, not allelic
Overall
CADD	13.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% African / African-American · 19/57,073 alleles

Filtering AF 0.0217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0181%

Overall 0.00183% 22/1,204,215 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,004
Admixed American	0.00445%	22,487
European (non-Finnish)	0.000112%	892,339

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: CD99L2
Protein: p.Val181Ala
Coding: c.542T>C
MANE Select: NM_031462
Type: single nucleotide variant
Location: chrX:150776287 (GRCh38)
Structure: AlphaFold pLDDT 55.71
Residue 181: the 'disordered' region

Full CD99L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD99L2 p.Asp175Asn Benign/Likely benign ★★ same type
CD99L2 c.203-9C>A Uncertain significance ★ same type
CD99L2 c.68-5755G>T Uncertain significance ★ same type
CD99L2 p.Ala182Ser Uncertain significance ★ ⚠ same type
CD99L2 p.Arg104Lys Uncertain significance ★ ⚠ same type
CD99L2 p.Arg131Gln Uncertain significance ★ ⚠ same type
CD99L2 p.Arg135Cys Uncertain significance ★ ⚠ same type
CD99L2 p.Arg169Gln 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/cd99l2-p-val181ala (accessed [today's date]).

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