Is CCDC74A p.Ser102Phe (c.305C>T) pathogenic?

CCDC74A p.Ser102Phe (c.305C>T) is classified Uncertain significance in CCDC74A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely benign (0.2889); Ultra-rare (popmax 0.027%, sas).

How common is CCDC74A p.Ser102Phe (c.305C>T) in the general population?

CCDC74A p.Ser102Phe (c.305C>T) is ultra-rare (popmax 0.027%, sas) (gnomAD).

What do computational predictors say about CCDC74A p.Ser102Phe (c.305C>T)?

AlphaMissense predicts likely benign (score 0.2889) — an in-silico prediction, not a clinical call.

CCDC74A p.Ser102Phe

c.305C>T · VCV3828774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2889 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2889	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -10.02	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 3.7	phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 3,695 bp · p 0.99 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S168F vs ClinVar S102F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.027% South Asian · 24/88,924 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.00175% 28/1,596,934 alleles · ultra-rare exomes 27/1,445,884 · genomes 1/151,050 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.027%	3,705
Remaining individualsnot grpmax-eligible	0.00162%	61,840
European (non-Finnish)	0.000255%	392,268

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: CCDC74A
Protein: p.Ser102Phe
Coding: c.305C>T
MANE Select: NM_001258306
Type: single nucleotide variant
Location: chr2:131530786 (GRCh38)
Gene constraint: LOEUF 1.366 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87
Residue 168 UniProt numbering: the 'disordered' region

Full CCDC74A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC74A c.296-114C>T Uncertain significance ★ ⚠ same type
CCDC74A c.296-121G>C Uncertain significance ★ ⚠ same type
CCDC74A c.296-12G>A Uncertain significance ★ ⚠ same type
CCDC74A c.296-130G>A Uncertain significance ★ ⚠ same type
CCDC74A c.296-139T>A Uncertain significance ★ ⚠ same type
CCDC74A c.296-147G>A Uncertain significance ★ ⚠ same type
CCDC74A c.296-151G>A Uncertain significance ★ ⚠ same type
CCDC74A c.296-154G>A 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/ccdc74a-p-ser102phe (accessed [today's date]).

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