Is CCDC181 p.Thr332Pro (c.994A>C) pathogenic?

CCDC181 p.Thr332Pro (c.994A>C) is classified Uncertain significance in CCDC181 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.2095); Very rare (popmax 0.00667%, amr).

How common is CCDC181 p.Thr332Pro (c.994A>C) in the general population?

CCDC181 p.Thr332Pro (c.994A>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CCDC181 p.Thr332Pro (c.994A>C)?

AlphaMissense predicts likely benign (score 0.2095) — an in-silico prediction, not a clinical call.

CCDC181 p.Thr332Pro

c.994A>C · rs41272449 · VCV2206344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2095	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 30 kb · p 0.0056 · regional, not allelic
Overall
CADD	24.3	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 0.00667% Admixed American · 4/59,984 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,996
Remaining individualsnot grpmax-eligible	0.0016%	62,500

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: CCDC181
Protein: p.Thr332Pro
Coding: c.994A>C
MANE Select: NM_001300969
dbSNP: rs41272449
Type: single nucleotide variant
Location: chr1:169421437 (GRCh38)
Gene constraint: LOEUF 0.85 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.92
Residue 332: the 'disordered' region

Full CCDC181 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC181 p.Thr332Ala Uncertain significance ★ ⚠ same residue
CCDC181 p.Ala292Thr Uncertain significance ★ ⚠ same type
CCDC181 p.Ala414Pro Uncertain significance ★ ⚠ same type
CCDC181 p.Ala41Val Uncertain significance ★ ⚠ same type
CCDC181 p.Arg150Gln Uncertain significance ★ ⚠ same type
CCDC181 p.Arg298Cys Uncertain significance ★ ⚠ same type
CCDC181 p.Arg310Gln Uncertain significance ★ ⚠ same type
CCDC181 p.Arg395Pro 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/ccdc181-p-thr332pro (accessed [today's date]).

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