Is CD99L2 p.Arg131Gln (c.392G>A) pathogenic?

CD99L2 p.Arg131Gln (c.392G>A) is classified Uncertain significance in CD99L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0801); Very rare (popmax 0.00179%, nfe).

How common is CD99L2 p.Arg131Gln (c.392G>A) in the general population?

CD99L2 p.Arg131Gln (c.392G>A) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about CD99L2 p.Arg131Gln (c.392G>A)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

CD99L2 p.Arg131Gln

c.392G>A · VCV4650774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.76	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 -7.6	GERP -4.3
Regional constraint	o/e 1.15	unconstrained · MANE · 130 kb · p 0.025 · regional, not allelic
Overall
CADD	0.063	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 0.00179% European (non-Finnish) · 16/895,274 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000856%

Overall 0.00149% 18/1,210,165 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,608
European (non-Finnish)grpmax	0.00179%	55,955
African / African-American	0.00175%	57,259

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: CD99L2
Protein: p.Arg131Gln
Coding: c.392G>A
MANE Select: NM_031462
Type: single nucleotide variant
Location: chrX:150795244 (GRCh38)
Structure: AlphaFold pLDDT 55.71
Residue 131: 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.Arg135Cys Uncertain significance ★ ⚠ same type
CD99L2 p.Arg169Gln Uncertain significance ★ ⚠ same type
CD99L2 p.Arg169Trp 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-arg131gln (accessed [today's date]).

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