Is CLIP2 p.Ala158Val (c.473C>T) pathogenic?

CLIP2 p.Ala158Val (c.473C>T) is classified Uncertain significance in CLIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0761); Very rare (popmax 0.00801%, afr).

How common is CLIP2 p.Ala158Val (c.473C>T) in the general population?

CLIP2 p.Ala158Val (c.473C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about CLIP2 p.Ala158Val (c.473C>T)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

CLIP2 p.Ala158Val

c.473C>T · VCV4229939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.52	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 4.6	GERP 6.3, phastCons 0.69
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.42 · regional, not allelic
Overall
CADD	17.9	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 0.00801% African / African-American · 6/74,920 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000807% 13/1,610,984 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
Admixed American	0.00334%	29,971
Remaining individualsnot grpmax-eligible	0.0032%	31,215
South Asian	0.0022%	45,511
Finnishnot grpmax-eligible	0.00163%	61,466

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: CLIP2
Protein: p.Ala158Val
Coding: c.473C>T
MANE Select: NM_003388
Type: single nucleotide variant
Location: chr7:74338799 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 2 PDB
Residue 158: the 'disordered' region

Full CLIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIP2 p.Ala158Pro Uncertain significance ★ ⚠ same residue
CLIP2 p.Arg12His Uncertain significance ★★ ⚠ same type
CLIP2 p.Ala123= Benign ★★ same type
CLIP2 p.Arg932= Benign ★★ same type
CLIP2 p.Asn205= Benign ★★ same type
CLIP2 p.Asn910= Benign/Likely benign ★★ same type
CLIP2 p.His159= Benign/Likely benign ★★ same type
CLIP2 p.Ile396= Benign ★★ 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/clip2-p-ala158val (accessed [today's date]).

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