Is CYTH4 p.Pro8Ala (c.22C>G) pathogenic?

CYTH4 p.Pro8Ala (c.22C>G) is classified Uncertain significance in CYTH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.0521); Ultra-rare (popmax 0.0165%, mid).

How common is CYTH4 p.Pro8Ala (c.22C>G) in the general population?

CYTH4 p.Pro8Ala (c.22C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CYTH4 p.Pro8Ala (c.22C>G)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

CYTH4 p.Pro8Ala

c.22C>G · VCV3499449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.07	GERP -3.8
Regional constraint	o/e 0.78	unconstrained · MANE · 31 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	9.305	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 0.0165% Middle Eastern · 1/6,054 alleles

Overall 0.000205% 3/1,461,354 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
Remaining individualsnot grpmax-eligible	0.0032%	31,245

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.Pro8Ala
Coding: c.22C>G
MANE Select: NM_013385
Type: single nucleotide variant
Location: chr22:37292623 (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-pro8ala (accessed [today's date]).

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