Is CLVS1 p.Thr15Pro (c.43A>C) pathogenic?

CLVS1 p.Thr15Pro (c.43A>C) is classified Uncertain significance in CLVS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.0648); Very rare (popmax 0.00178%, nfe).

How common is CLVS1 p.Thr15Pro (c.43A>C) in the general population?

CLVS1 p.Thr15Pro (c.43A>C) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about CLVS1 p.Thr15Pro (c.43A>C)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

CLVS1 p.Thr15Pro

c.43A>C · VCV4003979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -6.92	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 0.84	GERP -3.6
Regional constraint	o/e 1.14	unconstrained · MANE · 190 bp · p 0.23 · regional, not allelic
Overall
CADD	7.224	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 0.00178% European (non-Finnish) · 21/1,179,632 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00143% 23/1,613,332 alleles · very rare exomes 16/1,461,144 · genomes 7/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,173
Remaining individualsnot grpmax-eligible	0.0016%	62,446
African / African-American	0.00134%	74,870

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: CLVS1
Protein: p.Thr15Pro
Coding: c.43A>C
MANE Select: NM_173519
Type: single nucleotide variant
Location: chr8:61299870 (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-thr15pro (accessed [today's date]).

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