Is CCDC134 p.Pro181Ser (c.541C>T) pathogenic?

CCDC134 p.Pro181Ser (c.541C>T) is classified Uncertain significance in CCDC134 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.5563); Ultra-rare (popmax 0.033%, mid).

How common is CCDC134 p.Pro181Ser (c.541C>T) in the general population?

CCDC134 p.Pro181Ser (c.541C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CCDC134 p.Pro181Ser (c.541C>T)?

AlphaMissense predicts ambiguous (score 0.5563) — an in-silico prediction, not a clinical call.

CCDC134 p.Pro181Ser

c.541C>T · VCV4830980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5563 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Computational evidence

Protein change
AlphaMissense	0.5563	ambiguous
REVEL	0.429	indeterminate
SaProt	LLR -12.85	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 17 kb · p 0.13 · regional, not allelic
Overall
CADD	26.4	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00123% 18/1,461,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.0143%	7,006
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	8.47e-05%	1,180,020

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: CCDC134
Protein: p.Pro181Ser
Coding: c.541C>T
MANE Select: NM_024821
Type: single nucleotide variant
Location: chr22:41813799 (GRCh38)
Gene constraint: LOEUF 1.401 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 2 PDB

Full CCDC134 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC134 p.Arg121His Uncertain significance ★★ ⚠ same type
CCDC134 p.Met1Thr Pathogenic ★ same type
CCDC134 c.311-6C>T Uncertain significance ★ same type
CCDC134 p.Ala113Ser Uncertain significance ★ ⚠ same type
CCDC134 p.Arg121Cys Uncertain significance ★ ⚠ same type
CCDC134 p.Arg186Cys Uncertain significance ★ ⚠ same type
CCDC134 p.Arg186Gly Uncertain significance ★ ⚠ same type
CCDC134 p.Arg206His 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/ccdc134-p-pro181ser (accessed [today's date]).

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