Is CSH2 p.Ala46Val (c.137C>T) pathogenic?

CSH2 p.Ala46Val (c.137C>T) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). AlphaMissense: likely benign (0.141); Ultra-rare (popmax 0.0164%, mid).

How common is CSH2 p.Ala46Val (c.137C>T) in the general population?

CSH2 p.Ala46Val (c.137C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CSH2 p.Ala46Val (c.137C>T)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

CSH2 p.Ala46Val

c.137C>T · rs755600756 · VCV2603118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -6.49	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 9.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.14	constrained · MANE · 880 bp · p 6.3e-20 · regional, not allelic
Overall
CADD	18.96	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00279% 45/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Finnishnot grpmax-eligible	0.00312%	32,012
European (non-Finnish)	0.00305%	32,776
African / African-American	0.00267%	37,478
South Asian	0.0011%	91,090

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.Ala46Val
Coding: c.137C>T
MANE Select: NM_020991
dbSNP: rs755600756
Type: single nucleotide variant
Location: chr17:63873213 (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.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
CSH2 p.Arg204His 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-ala46val (accessed [today's date]).

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