Is CD99L2 p.Trp46Arg (c.136T>C) pathogenic?

CD99L2 p.Trp46Arg (c.136T>C) is classified Uncertain significance in CD99L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: ambiguous (0.3797); Absent from gnomAD v4.1.

How common is CD99L2 p.Trp46Arg (c.136T>C) in the general population?

CD99L2 p.Trp46Arg (c.136T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD99L2 p.Trp46Arg (c.136T>C)?

AlphaMissense predicts ambiguous (score 0.3797) — an in-silico prediction, not a clinical call.

CD99L2 p.Trp46Arg

c.136T>C · VCV4650779

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3797 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3797	ambiguous
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 130 kb · p 0.025 · regional, not allelic
Overall
CADD	18.04	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CD99L2
Protein: p.Trp46Arg
Coding: c.136T>C
MANE Select: NM_031462
Type: single nucleotide variant
Location: chrX:150816073 (GRCh38)
Structure: AlphaFold pLDDT 55.71
Residue 46: 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-trp46arg (accessed [today's date]).

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