Is CISH p.Arg78Gln (c.233G>A) pathogenic?

CISH p.Arg78Gln (c.233G>A) is classified Likely benign in CISH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-03-01). AlphaMissense: likely benign (0.1024); Low-frequency (popmax 1.1%, eas).

How common is CISH p.Arg78Gln (c.233G>A) in the general population?

CISH p.Arg78Gln (c.233G>A) is low-frequency (popmax 1.1%, eas) (gnomAD).

What do computational predictors say about CISH p.Arg78Gln (c.233G>A)?

AlphaMissense predicts likely benign (score 0.1024) — an in-silico prediction, not a clinical call.

CISH p.Arg78Gln

c.233G>A · rs148162012 · VCV723118

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1024 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.1%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1024	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -5.39	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 3.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,040 bp · p 0.00013 · regional, not allelic
Overall
CADD	22.4	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 1.1% East Asian · 492/44,778 alleles

Filtering AF 1.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.987%

Overall 0.0507% 811/1,600,448 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.1%	91
Ashkenazi Jewishnot grpmax-eligible	0.408%	245
Remaining individualsnot grpmax-eligible	0.063%	1,587
South Asian	0.0326%	3,071
European (non-Finnish)	0.0111%	9,027
Admixed American	0.00523%	19,125
Finnishnot grpmax-eligible	0.00157%	63,664

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.Arg78Gln
Coding: c.233G>A
MANE Select: NM_145071
dbSNP: rs148162012
Type: single nucleotide variant
Location: chr3:50608381 (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.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
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-arg78gln (accessed [today's date]).

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