Is CISH p.Arg149Cys (c.445C>T) pathogenic?

CISH p.Arg149Cys (c.445C>T) is classified Uncertain significance in CISH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-06). AlphaMissense: likely benign (0.304); Ultra-rare (popmax 0.0169%, nfe).

How common is CISH p.Arg149Cys (c.445C>T) in the general population?

CISH p.Arg149Cys (c.445C>T) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about CISH p.Arg149Cys (c.445C>T)?

AlphaMissense predicts likely benign (score 0.304) — an in-silico prediction, not a clinical call.

CISH p.Arg149Cys

c.445C>T · VCV3493083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.304	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -8.92	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,040 bp · p 0.00013 · regional, not allelic
Overall
CADD	28.7	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 0.0169% European (non-Finnish) · 199/1,180,012 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0142%

Overall 0.0143% 209/1,461,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,930
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
Remaining individualsnot grpmax-eligible	0.008%	12,501
African / African-American	0.00133%	75,020

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: CISH
Protein: p.Arg149Cys
Coding: c.445C>T
MANE Select: NM_145071
Type: single nucleotide variant
Location: chr3:50607939 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.91
Residue 149: the sh2 domain

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

Similar variants

CISH p.Arg78Gln Likely benign ★★ same type
CISH p.Leu223= Benign ★★ same type
CISH p.Ser173= Benign/Likely benign ★★ same type
CISH c.20+1222A>G Uncertain significance ★ same type
CISH c.20+1236G>A Uncertain significance ★ same type
CISH c.20+1246C>A Uncertain significance ★ same type
CISH p.Arg107His Uncertain significance ★ ⚠ same type
CISH p.Arg130Cys 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/cish-p-arg149cys (accessed [today's date]).

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