Is CLVS2 p.Ala139Gly (c.416C>G) pathogenic?

CLVS2 p.Ala139Gly (c.416C>G) is classified Uncertain significance in CLVS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: ambiguous (0.3415); Absent from gnomAD v4.1.

How common is CLVS2 p.Ala139Gly (c.416C>G) in the general population?

CLVS2 p.Ala139Gly (c.416C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLVS2 p.Ala139Gly (c.416C>G)?

AlphaMissense predicts ambiguous (score 0.3415) — an in-silico prediction, not a clinical call.

CLVS2 p.Ala139Gly

c.416C>G · rs2534529089 · VCV3146176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3415 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3415	ambiguous
REVEL	0.681	pathogenic-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 58 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	27.1	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: CLVS2
Protein: p.Ala139Gly
Coding: c.416C>G
MANE Select: NM_001010852
dbSNP: rs2534529089
Type: single nucleotide variant
Location: chr6:123011011 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.15
Residue 139: the cral-trio domain

Full CLVS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLVS2 p.Ala146Thr Uncertain significance ★ ⚠ same type
CLVS2 p.Arg138Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Arg215Trp Uncertain significance ★ ⚠ same type
CLVS2 p.Arg48Cys Uncertain significance ★ ⚠ same type
CLVS2 p.Asp272Gly Uncertain significance ★ ⚠ same type
CLVS2 p.Glu19Gln Uncertain significance ★ ⚠ same type
CLVS2 p.Glu316Gly Uncertain significance ★ ⚠ same type
CLVS2 p.His241Asn 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/clvs2-p-ala139gly (accessed [today's date]).

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