Is CCDC174 p.Pro158Ser (c.472C>T) pathogenic?

CCDC174 p.Pro158Ser (c.472C>T) is classified Uncertain significance in CCDC174 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-05-21). AlphaMissense: likely benign (0.1171); Rare (popmax 0.22%, nfe); Associated with severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome.

How common is CCDC174 p.Pro158Ser (c.472C>T) in the general population?

CCDC174 p.Pro158Ser (c.472C>T) is rare (popmax 0.22%, nfe) (gnomAD).

What do computational predictors say about CCDC174 p.Pro158Ser (c.472C>T)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

CCDC174 p.Pro158Ser

Q: What condition is associated with CCDC174 p.Pro158Ser (c.472C>T)?

CCDC174 p.Pro158Ser (c.472C>T) is associated with severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome (ClinVar).

Q: How is Severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.472C>T · rs145180886 · VCV1029605

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.22%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -10.10	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 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 19 kb · p 0.15 · regional, not allelic
Overall
CADD	23.2	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 0.22% European (non-Finnish) · 2,591/1,179,322 alleles

Filtering AF 0.213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.21%

Overall 0.173% 2,781/1,611,986 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.22%	455
Remaining individualsnot grpmax-eligible	0.147%	678
Finnishnot grpmax-eligible	0.0844%	1,185
Middle Eastern	0.0662%	1,512
African / African-American	0.0441%	2,267
Admixed American	0.0118%	8,482

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.Pro158Ser
Coding: c.472C>T
MANE Select: NM_016474
dbSNP: rs145180886
Type: single nucleotide variant
Location: chr3:14661694 (GRCh38)
Gene constraint: LOEUF 0.926 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79
Residue 158: the 'disordered' region

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

Disease context

severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

CCDC174 p.Asp395His Uncertain significance ★★ ⚠ same condition
CCDC174 p.Phe29Ser Uncertain significance ★★ ⚠ same condition
CCDC174 c.308-55C>A Benign ★★ same condition
CCDC174 c.485+83C>G Benign ★★ same condition
CCDC174 c.725-13A>G Benign ★★ same condition
CCDC174 p.Pro392= Benign ★★ same condition
CCDC174 p.Val348= Benign/Likely benign ★★ same condition
CCDC174 p.Arg174Leu Uncertain significance ★ ⚠ same condition

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-pro158ser (accessed [today's date]).

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