Is CCDC174 p.Val166Met (c.496G>A) pathogenic?

CCDC174 p.Val166Met (c.496G>A) is classified Uncertain significance in CCDC174 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: ambiguous (0.3774); Ultra-rare (popmax 0.0383%, amr).

How common is CCDC174 p.Val166Met (c.496G>A) in the general population?

CCDC174 p.Val166Met (c.496G>A) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about CCDC174 p.Val166Met (c.496G>A)?

AlphaMissense predicts ambiguous (score 0.3774) — an in-silico prediction, not a clinical call.

CCDC174 p.Val166Met

c.496G>A · rs374255925 · VCV2598892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Computational evidence

Protein change
AlphaMissense	0.3774	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -9.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.62, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 19 kb · p 0.15 · regional, not allelic
Overall
CADD	28.4	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 0.0383% Admixed American · 23/60,012 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00359% 58/1,613,460 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,609
African / African-American	0.00267%	37,494
European (non-Finnish)	0.00263%	38,047
South Asian	0.0022%	45,533

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: CCDC174
Protein: p.Val166Met
Coding: c.496G>A
MANE Select: NM_016474
dbSNP: rs374255925
Type: single nucleotide variant
Location: chr3:14665038 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79

Full CCDC174 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC174 p.Asp395His Uncertain significance ★★ ⚠ same type
CCDC174 p.Phe29Ser Uncertain significance ★★ ⚠ same type
CCDC174 p.Pro158Ser Uncertain significance ★★ ⚠ same type
CCDC174 c.1106-10T>A Benign/Likely benign ★★ same type
CCDC174 c.308-55C>A Benign ★★ same type
CCDC174 c.485+47G>A Benign ★★ same type
CCDC174 c.485+83C>G Benign ★★ same type
CCDC174 c.485+83C>T Benign ★★ 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/ccdc174-p-val166met (accessed [today's date]).

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