Is CISH p.Arg221His (c.662G>A) pathogenic?

CISH p.Arg221His (c.662G>A) is classified Uncertain significance in CISH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.1338); Rare (popmax 0.28%, mid).

How common is CISH p.Arg221His (c.662G>A) in the general population?

CISH p.Arg221His (c.662G>A) is rare (popmax 0.28%, mid) (gnomAD).

What do computational predictors say about CISH p.Arg221His (c.662G>A)?

AlphaMissense predicts likely benign (score 0.1338) — an in-silico prediction, not a clinical call.

CISH p.Arg221His

c.662G>A · rs139699451 · VCV2292832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1338 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1338	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -2.36	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 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,040 bp · p 0.00013 · regional, not allelic
Overall
CADD	27.4	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 0.28% Middle Eastern · 17/6,062 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0323% 522/1,613,868 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	357
Remaining individualsnot grpmax-eligible	0.0432%	2,314
European (non-Finnish)	0.0372%	2,688
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
South Asian	0.0198%	5,060
Admixed American	0.01%	10,004
East Asian	0.00446%	22,443
African / African-American	0.004%	25,015
Finnishnot grpmax-eligible	0.00157%	63,848

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.Arg221His
Coding: c.662G>A
MANE Select: NM_145071
dbSNP: rs139699451
Type: single nucleotide variant
Location: chr3:50607722 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.91
Residue 221: the socs box 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-arg221his (accessed [today's date]).

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