Is CCDC74A p.Pro282Ser (c.844C>T) pathogenic?

CCDC74A p.Pro282Ser (c.844C>T) is classified Uncertain significance in CCDC74A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely pathogenic (0.845); Ultra-rare (popmax 0.0587%, afr).

How common is CCDC74A p.Pro282Ser (c.844C>T) in the general population?

CCDC74A p.Pro282Ser (c.844C>T) is ultra-rare (popmax 0.0587%, afr) (gnomAD).

What do computational predictors say about CCDC74A p.Pro282Ser (c.844C>T)?

AlphaMissense predicts likely pathogenic (score 0.845) — an in-silico prediction, not a clinical call.

CCDC74A p.Pro282Ser

c.844C>T · rs377579678 · VCV2347715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0587%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.845	likely pathogenic · top 6% in CCDC74A
REVEL	0.348	indeterminate
SaProt	LLR -0.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,683 bp · p 0.0022 · regional, not allelic
Overall
CADD	23.7	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 P348S vs ClinVar P282S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0587% African / African-American · 44/74,930 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.00335% 54/1,613,170 alleles · ultra-rare exomes 26/1,460,962 · genomes 28/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0587%	1,703
Admixed American	0.00667%	14,998
Remaining individualsnot grpmax-eligible	0.0048%	20,815
South Asian	0.00329%	30,353

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.Pro282Ser
Coding: c.844C>T
MANE Select: NM_001258306
dbSNP: rs377579678
Type: single nucleotide variant
Location: chr2:131533303 (GRCh38)
Gene constraint: LOEUF 1.366 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.87

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-pro282ser (accessed [today's date]).

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