Is CYTH4 p.Arg26Gln (c.77G>A) pathogenic?

CYTH4 p.Arg26Gln (c.77G>A) is classified Uncertain significance in CYTH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1691); Very rare (popmax 0.00223%, eas).

How common is CYTH4 p.Arg26Gln (c.77G>A) in the general population?

CYTH4 p.Arg26Gln (c.77G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CYTH4 p.Arg26Gln (c.77G>A)?

AlphaMissense predicts likely benign (score 0.1691) — an in-silico prediction, not a clinical call.

CYTH4 p.Arg26Gln

c.77G>A · VCV4658284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1691	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -9.58	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 12	GERP 0.87, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 31 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00164% 24/1,461,468 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	0.00186%	53,634
Admixed American	0.00167%	60,026

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.Arg26Gln
Coding: c.77G>A
MANE Select: NM_013385
Type: single nucleotide variant
Location: chr22:37292678 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 87.17

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

Similar variants

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
CYTH4 p.Arg212Cys 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-arg26gln (accessed [today's date]).

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