Is CYTH2 p.Gly331Arg (c.991G>A) pathogenic?

CYTH2 p.Gly331Arg (c.991G>A) is classified Uncertain significance in CYTH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-21). AlphaMissense: likely pathogenic (0.8701); Very rare (popmax 0.00212%, nfe).

How common is CYTH2 p.Gly331Arg (c.991G>A) in the general population?

CYTH2 p.Gly331Arg (c.991G>A) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about CYTH2 p.Gly331Arg (c.991G>A)?

AlphaMissense predicts likely pathogenic (score 0.8701) — an in-silico prediction, not a clinical call.

CYTH2 p.Gly331Arg

c.991G>A · rs765967604 · VCV2527446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8701	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 9,699 bp · p 1.7e-11 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G332R vs ClinVar G331R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,180,012 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00171% 25/1,461,844 alleles · very rare

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: CYTH2
Protein: p.Gly331Arg
Coding: c.991G>A
MANE Select: NM_004228
dbSNP: rs765967604
Type: single nucleotide variant
Location: chr19:48478471 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI 0.13 (gnomAD)
Structure: AlphaFold pLDDT 85.02 · 11 PDB
Residue 331: the ph domain

Full CYTH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYTH2 p.Ala168Thr Uncertain significance ★ ⚠ same type
CYTH2 p.Ala385Val Uncertain significance ★ ⚠ same type
CYTH2 p.Arg212His Uncertain significance ★ ⚠ same type
CYTH2 p.Arg232Thr Uncertain significance ★ ⚠ same type
CYTH2 p.Arg262Gln Uncertain significance ★ ⚠ same type
CYTH2 p.Arg344Gln Uncertain significance ★ ⚠ same type
CYTH2 p.Arg35Cys Uncertain significance ★ ⚠ same type
CYTH2 p.Arg61Gln 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/cyth2-p-gly331arg (accessed [today's date]).

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