Is CSH2 p.Val211Leu (c.631G>C) pathogenic?

CSH2 p.Val211Leu (c.631G>C) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely benign (0.2687); Absent from gnomAD v4.1.

How common is CSH2 p.Val211Leu (c.631G>C) in the general population?

CSH2 p.Val211Leu (c.631G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CSH2 p.Val211Leu (c.631G>C)?

AlphaMissense predicts likely benign (score 0.2687) — an in-silico prediction, not a clinical call.

CSH2 p.Val211Leu

c.631G>C · VCV4656978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2687 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2687	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -8.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.51, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 604 bp · p 0.31 · regional, not allelic
Overall
CADD	18.18	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

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: CSH2
Protein: p.Val211Leu
Coding: c.631G>C
MANE Select: NM_020991
Type: single nucleotide variant
Location: chr17:63872149 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.15
Residue 211: a disulfide bond

Full CSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSH2 p.Ter218Gln Benign ★★ same type
CSH2 p.Ala39Thr Uncertain significance ★ ⚠ same type
CSH2 p.Ala46Val Uncertain significance ★ ⚠ same type
CSH2 p.Arg103Cys Uncertain significance ★ ⚠ same type
CSH2 p.Arg117Trp Uncertain significance ★ ⚠ same type
CSH2 p.Arg159Cys Uncertain significance ★ ⚠ same type
CSH2 p.Arg160Gln Uncertain significance ★ ⚠ same type
CSH2 p.Arg160Trp 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/csh2-p-val211leu (accessed [today's date]).

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