Is CYTH4 p.Arg232Gln (c.695G>A) pathogenic?

CYTH4 p.Arg232Gln (c.695G>A) is classified Uncertain significance in CYTH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). AlphaMissense: likely benign (0.0811); Very rare (popmax 0.00373%, nfe).

How common is CYTH4 p.Arg232Gln (c.695G>A) in the general population?

CYTH4 p.Arg232Gln (c.695G>A) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about CYTH4 p.Arg232Gln (c.695G>A)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

CYTH4 p.Arg232Gln

c.695G>A · rs200267703 · VCV3079823

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 0.93, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 31 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	24.8	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 0.00373% European (non-Finnish) · 44/1,179,470 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00304% 49/1,612,526 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,801
European (non-Finnish)grpmax	0.00373%	26,806
Admixed American	0.00168%	59,680
South Asian	0.0011%	91,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CYTH4
Protein: p.Arg232Gln
Coding: c.695G>A
MANE Select: NM_013385
dbSNP: rs200267703
Type: single nucleotide variant
Location: chr22:37303401 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 87.17
Residue 232: the sec7 domain

Full CYTH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYTH4 p.Arg232Trp Uncertain significance ★ ⚠ same residue
CYTH4 p.Asn107His Benign ★★ ⚠ same type
CYTH4 p.Leu88= Benign ★★ same type
CYTH4 p.Met74Val Benign ★★ same type
CYTH4 p.Ala136Thr Uncertain significance ★ ⚠ same type
CYTH4 p.Ala166Val Uncertain significance ★ ⚠ same type
CYTH4 p.Ala9Glu Uncertain significance ★ ⚠ same type
CYTH4 p.Arg205Gln 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/cyth4-p-arg232gln (accessed [today's date]).

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