Is CSH2 p.Val30Ile (c.88G>A) pathogenic?

CSH2 p.Val30Ile (c.88G>A) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.0969); Ultra-rare (popmax 0.028%, afr).

How common is CSH2 p.Val30Ile (c.88G>A) in the general population?

CSH2 p.Val30Ile (c.88G>A) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about CSH2 p.Val30Ile (c.88G>A)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

CSH2 p.Val30Ile

c.88G>A · rs371058095 · VCV2391387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -5.29	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 -0.13	GERP -3, phastCons 0.034
Regional constraint	o/e 0.14	constrained · MANE · 880 bp · p 6.3e-20 · regional, not allelic
Overall
CADD	6.181	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 0.028% African / African-American · 21/75,088 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00366% 59/1,614,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,576
Admixed American	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.0064%	15,626
South Asian	0.00439%	22,769
Finnishnot grpmax-eligible	0.00312%	32,023
European (non-Finnish)	0.00186%	53,636

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: CSH2
Protein: p.Val30Ile
Coding: c.88G>A
MANE Select: NM_020991
dbSNP: rs371058095
Type: single nucleotide variant
Location: chr17:63873262 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.15

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-val30ile (accessed [today's date]).

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