Is CLVS1 p.Leu235Phe (c.703C>T) pathogenic?

CLVS1 p.Leu235Phe (c.703C>T) is classified Uncertain significance in CLVS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-27). AlphaMissense: ambiguous (0.5566); Ultra-rare (popmax 0.0133%, afr).

How common is CLVS1 p.Leu235Phe (c.703C>T) in the general population?

CLVS1 p.Leu235Phe (c.703C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about CLVS1 p.Leu235Phe (c.703C>T)?

AlphaMissense predicts ambiguous (score 0.5566) — an in-silico prediction, not a clinical call.

CLVS1 p.Leu235Phe

c.703C>T · rs374404656 · VCV2521466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Computational evidence

Protein change
AlphaMissense	0.5566	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -7.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.18, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 158 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.0133% African / African-American · 10/74,918 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00105% 17/1,613,956 alleles · ultra-rare exomes 9/1,461,766 · genomes 8/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,492
Admixed American	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	8.48e-05%	1,179,935

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.Leu235Phe
Coding: c.703C>T
MANE Select: NM_173519
dbSNP: rs374404656
Type: single nucleotide variant
Location: chr8:61454213 (GRCh38)
Gene constraint: LOEUF 0.473 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 82.01
Residue 235: the cral-trio domain

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-leu235phe (accessed [today's date]).

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