Is CSH2 p.Gly25Arg (c.73G>C) pathogenic?

CSH2 p.Gly25Arg (c.73G>C) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.2302); Ultra-rare (popmax 0.0283%, amr).

How common is CSH2 p.Gly25Arg (c.73G>C) in the general population?

CSH2 p.Gly25Arg (c.73G>C) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about CSH2 p.Gly25Arg (c.73G>C)?

AlphaMissense predicts likely benign (score 0.2302) — an in-silico prediction, not a clinical call.

CSH2 p.Gly25Arg

c.73G>C · rs752023583 · VCV2290420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2302 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2302	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -5.45	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 0.022	GERP -3.7
Regional constraint	o/e 0.14	constrained · MANE · 880 bp · p 6.3e-20 · regional, not allelic
Overall
CADD	17.67	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 0.0283% Admixed American · 17/60,006 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00105% 17/1,614,100 alleles · ultra-rare

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.Gly25Arg
Coding: c.73G>C
MANE Select: NM_020991
dbSNP: rs752023583
Type: single nucleotide variant
Location: chr17:63873277 (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-gly25arg (accessed [today's date]).

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