Is CISH p.Arg16Gln (c.47G>A) pathogenic?

CISH p.Arg16Gln (c.47G>A) is classified Likely benign in CISH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely benign (0.061); Ultra-rare (popmax 0.0122%, sas).

How common is CISH p.Arg16Gln (c.47G>A) in the general population?

CISH p.Arg16Gln (c.47G>A) is ultra-rare (popmax 0.0122%, sas) (gnomAD).

What do computational predictors say about CISH p.Arg16Gln (c.47G>A)?

AlphaMissense predicts likely benign (score 0.061) — an in-silico prediction, not a clinical call.

CISH p.Arg16Gln

c.47G>A · VCV3267441

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.061	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.75	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 -4.2	GERP -5.6
Regional constraint	o/e 0.80	unconstrained · MANE · 4,040 bp · p 0.00013 · regional, not allelic
Overall
CADD	0.233	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% South Asian · 10/81,820 alleles

Filtering AF 0.00656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00499%

Overall 0.00271% 42/1,552,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0122%	8,182
Finnishnot grpmax-eligible	0.012%	8,309
East Asian	0.00681%	14,679
African / African-American	0.00547%	18,290
Remaining individualsnot grpmax-eligible	0.00501%	19,941
European (non-Finnish)	0.0013%	76,818

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.Arg16Gln
Coding: c.47G>A
MANE Select: NM_145071
Type: single nucleotide variant
Location: chr3:50608567 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.91

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

Similar variants

CISH p.Arg16Trp Uncertain significance ★ ⚠ same residue
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

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-arg16gln (accessed [today's date]).

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