Is CCDC174 p.Pro421Ser (c.1261C>T) pathogenic?

CCDC174 p.Pro421Ser (c.1261C>T) is classified Uncertain significance in CCDC174 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0646); Ultra-rare (popmax 0.0102%, nfe).

How common is CCDC174 p.Pro421Ser (c.1261C>T) in the general population?

CCDC174 p.Pro421Ser (c.1261C>T) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about CCDC174 p.Pro421Ser (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

CCDC174 p.Pro421Ser

c.1261C>T · rs558741704 · VCV3138866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.41	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 -2.2	GERP -3.4
Regional constraint	o/e 0.94	unconstrained · MANE · 19 kb · p 0.15 · regional, not allelic
Overall
CADD	0.452	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 0.0102% European (non-Finnish) · 120/1,180,010 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00762% 123/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,833
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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.Pro421Ser
Coding: c.1261C>T
MANE Select: NM_016474
dbSNP: rs558741704
Type: single nucleotide variant
Location: chr3:14671051 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79
Residue 421: the 'disordered' region

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-pro421ser (accessed [today's date]).

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