Is CSH2 p.Arg160Trp (c.478C>T) pathogenic?

CSH2 p.Arg160Trp (c.478C>T) is classified Uncertain significance in CSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.1041); Ultra-rare (popmax 0.0986%, afr).

How common is CSH2 p.Arg160Trp (c.478C>T) in the general population?

CSH2 p.Arg160Trp (c.478C>T) is ultra-rare (popmax 0.0986%, afr) (gnomAD).

What do computational predictors say about CSH2 p.Arg160Trp (c.478C>T)?

AlphaMissense predicts likely benign (score 0.1041) — an in-silico prediction, not a clinical call.

CSH2 p.Arg160Trp

c.478C>T · rs184890744 · VCV2383594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1041 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1041	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -8.31	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 1.4	GERP -0.44, phastCons 0.82
Regional constraint	o/e 0.92	unconstrained · MANE · 604 bp · p 0.31 · regional, not allelic
Overall
CADD	20.6	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 0.0986% African / African-American · 74/75,050 alleles

Filtering AF 0.0805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0738%

Overall 0.00682% 110/1,613,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0986%	1,014
Admixed American	0.0233%	4,287
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
Remaining individualsnot grpmax-eligible	0.008%	12,495
East Asian	0.00223%	44,884
South Asian	0.0011%	91,072
European (non-Finnish)	0.00102%	98,316

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.Arg160Trp
Coding: c.478C>T
MANE Select: NM_020991
dbSNP: rs184890744
Type: single nucleotide variant
Location: chr17:63872302 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.15
Residue 160: a disulfide bond

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

Similar variants

CSH2 p.Arg160Gln Uncertain significance ★ ⚠ same residue
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.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-arg160trp (accessed [today's date]).

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