Is CCDC158 p.Ser63Phe (c.188C>T) pathogenic?

CCDC158 p.Ser63Phe (c.188C>T) is classified Uncertain significance in CCDC158 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1032); Very rare (popmax 0.00509%, nfe).

How common is CCDC158 p.Ser63Phe (c.188C>T) in the general population?

CCDC158 p.Ser63Phe (c.188C>T) is very rare (popmax 0.00509%, nfe) (gnomAD).

What do computational predictors say about CCDC158 p.Ser63Phe (c.188C>T)?

AlphaMissense predicts likely benign (score 0.1032) — an in-silico prediction, not a clinical call.

CCDC158 p.Ser63Phe

c.188C>T · rs761629412 · VCV2460515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00509%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1032	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -9.18	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 8.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 90 kb · p 0.26 · regional, not allelic
Overall
CADD	23.7	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 0.00509% European (non-Finnish) · 60/1,179,556 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.0039% 63/1,613,416 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00509%	19,659
African / African-American	0.00267%	37,443
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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: CCDC158
Protein: p.Ser63Phe
Coding: c.188C>T
MANE Select: NM_001394954
dbSNP: rs761629412
Type: single nucleotide variant
Location: chr4:76396369 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.43

Full CCDC158 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC158 p.Ala1046Pro Uncertain significance ★ ⚠ same type
CCDC158 p.Ala336Ser Uncertain significance ★ ⚠ same type
CCDC158 p.Ala451Thr Uncertain significance ★ ⚠ same type
CCDC158 p.Ala452Ser Uncertain significance ★ ⚠ same type
CCDC158 p.Ala468Asp Uncertain significance ★ ⚠ same type
CCDC158 p.Ala618Thr Uncertain significance ★ ⚠ same type
CCDC158 p.Ala704Thr Uncertain significance ★ ⚠ same type
CCDC158 p.Ala704Val 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/ccdc158-p-ser63phe (accessed [today's date]).

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