Is CISH p.Arg107His (c.320G>A) pathogenic?

CISH p.Arg107His (c.320G>A) is classified Uncertain significance in CISH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9945); Very rare (popmax 0.00167%, amr).

How common is CISH p.Arg107His (c.320G>A) in the general population?

CISH p.Arg107His (c.320G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CISH p.Arg107His (c.320G>A)?

AlphaMissense predicts likely pathogenic (score 0.9945) — an in-silico prediction, not a clinical call.

CISH p.Arg107His

c.320G>A · VCV4229142

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9945 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9945	likely pathogenic · top 5% in CISH
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -14.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,040 bp · p 0.00013 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,000 alleles

Overall 0.000248% 4/1,613,604 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
African / African-American	0.00134%	74,902
South Asian	0.0011%	91,090
European (non-Finnish)	8.48e-05%	1,179,915

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.Arg107His
Coding: c.320G>A
MANE Select: NM_145071
Type: single nucleotide variant
Location: chr3:50608064 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.91
Residue 107: 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.Arg130Cys Uncertain significance ★ ⚠ same type
CISH p.Arg139His 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-arg107his (accessed [today's date]).

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