Is CCDC92 p.Val221Phe (c.661G>T) pathogenic?

CCDC92 p.Val221Phe (c.661G>T) is classified Uncertain significance in CCDC92 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely benign (0.303); Very rare (popmax 0.00223%, eas).

How common is CCDC92 p.Val221Phe (c.661G>T) in the general population?

CCDC92 p.Val221Phe (c.661G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCDC92 p.Val221Phe (c.661G>T)?

AlphaMissense predicts likely benign (score 0.303) — an in-silico prediction, not a clinical call.

CCDC92 p.Val221Phe

c.661G>T · VCV3997402

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.303 · 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	0.303	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.34	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 3.1	GERP 0.52, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,244 bp · p 0.054 · regional, not allelic
Overall
CADD	24.2	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 · 1/44,884 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,862 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
European (non-Finnish)	0.00102%	98,336

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: CCDC92
Protein: p.Val221Phe
Coding: c.661G>T
MANE Select: NM_025140
Type: single nucleotide variant
Location: chr12:123937393 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 73.80

Full CCDC92 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC92 p.Ala114Thr Uncertain significance ★ ⚠ same type
CCDC92 p.Ala178Asp Uncertain significance ★ ⚠ same type
CCDC92 p.Ala226Val Uncertain significance ★ ⚠ same type
CCDC92 p.Ala269Thr Uncertain significance ★ ⚠ same type
CCDC92 p.Ala93Val Uncertain significance ★ ⚠ same type
CCDC92 p.Arg203His Uncertain significance ★ ⚠ same type
CCDC92 p.Arg223Gly Uncertain significance ★ ⚠ same type
CCDC92 p.Arg234Gln 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/ccdc92-p-val221phe (accessed [today's date]).

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