Is CCDC74A p.Ser28Phe (c.83C>T) pathogenic?

CCDC74A p.Ser28Phe (c.83C>T) is classified Uncertain significance in CCDC74A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.2088); Ultra-rare (popmax 0.0137%, eas).

How common is CCDC74A p.Ser28Phe (c.83C>T) in the general population?

CCDC74A p.Ser28Phe (c.83C>T) is ultra-rare (popmax 0.0137%, eas) (gnomAD).

What do computational predictors say about CCDC74A p.Ser28Phe (c.83C>T)?

AlphaMissense predicts likely benign (score 0.2088) — an in-silico prediction, not a clinical call.

CCDC74A p.Ser28Phe

c.83C>T · rs750083391 · VCV2216513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2088 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2088	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.61	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 0.82	phastCons 0.019
Regional constraint	o/e 1.00	unconstrained · MANE · 3,695 bp · p 0.99 · regional, not allelic
Overall
CADD	18.75	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 0.0137% East Asian · 6/43,932 alleles

Filtering AF 0.00589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00401%

Overall 0.000497% 7/1,408,804 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0137%	7,322
European (non-Finnish)	8.61e-05%	1,161,466

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.Ser28Phe
Coding: c.83C>T
MANE Select: NM_001258306
dbSNP: rs750083391
Type: single nucleotide variant
Location: chr2:131528053 (GRCh38)
Gene constraint: LOEUF 1.366 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87
Residue 28: 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-ser28phe (accessed [today's date]).

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