Is CLVS1 p.Leu42Pro (c.125T>C) pathogenic?

CLVS1 p.Leu42Pro (c.125T>C) is classified Uncertain significance in CLVS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1.

How common is CLVS1 p.Leu42Pro (c.125T>C) in the general population?

CLVS1 p.Leu42Pro (c.125T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLVS1 p.Leu42Pro (c.125T>C)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CLVS1 p.Leu42Pro

c.125T>C · rs2487222639 · VCV3146171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic · top 6% in CLVS1
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -14.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 190 bp · p 0.23 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: CLVS1
Protein: p.Leu42Pro
Coding: c.125T>C
MANE Select: NM_173519
dbSNP: rs2487222639
Type: single nucleotide variant
Location: chr8:61299952 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.01

Full CLVS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLVS1 p.Ala28Ser Uncertain significance ★ ⚠ same type
CLVS1 p.Arg39Cys Uncertain significance ★ ⚠ same type
CLVS1 p.Asn153Asp Uncertain significance ★ ⚠ same type
CLVS1 p.Asn178Ser Uncertain significance ★ ⚠ same type
CLVS1 p.Asn224Ser Uncertain significance ★ ⚠ same type
CLVS1 p.Asn346Thr Uncertain significance ★ ⚠ same type
CLVS1 p.Asp106Asn Uncertain significance ★ ⚠ same type
CLVS1 p.Asp114Asn 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/clvs1-p-leu42pro (accessed [today's date]).

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