Is CSH1 p.Val211Ala (c.632T>C) pathogenic?

CSH1 p.Val211Ala (c.632T>C) is classified Uncertain significance in CSH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.1825); Ultra-rare (popmax 0.0495%, mid).

How common is CSH1 p.Val211Ala (c.632T>C) in the general population?

CSH1 p.Val211Ala (c.632T>C) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CSH1 p.Val211Ala (c.632T>C)?

AlphaMissense predicts likely benign (score 0.1825) — an in-silico prediction, not a clinical call.

CSH1 p.Val211Ala

c.632T>C · VCV3836717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1825	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -11.06	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -0.62, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 1,060 bp · p 0.37 · regional, not allelic
Overall
CADD	17.05	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000479% 7/1,461,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
European (non-Finnish)	0.000339%	294,916

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: CSH1
Protein: p.Val211Ala
Coding: c.632T>C
MANE Select: NM_001317
Type: single nucleotide variant
Location: chr17:63895044 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.67 · 1 PDB
Residue 211: a disulfide bond

Full CSH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSH1 p.Val211Leu Uncertain significance ★ ⚠ same residue
CSH1 p.Ala14Gly Uncertain significance ★ ⚠ same type
CSH1 p.Ala2Thr Uncertain significance ★ ⚠ same type
CSH1 p.Arg159His Uncertain significance ★ ⚠ same type
CSH1 p.Arg160Trp Uncertain significance ★ ⚠ same type
CSH1 p.Arg204Ser Uncertain significance ★ ⚠ same type
CSH1 p.Arg6Gln Uncertain significance ★ ⚠ same type
CSH1 p.Asp135Asn 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/csh1-p-val211ala (accessed [today's date]).

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