Is CCDC137 p.Ala9Glu (c.26C>A) pathogenic?

CCDC137 p.Ala9Glu (c.26C>A) is classified Uncertain significance in CCDC137 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1548); Ultra-rare (popmax 0.0103%, amr).

How common is CCDC137 p.Ala9Glu (c.26C>A) in the general population?

CCDC137 p.Ala9Glu (c.26C>A) is ultra-rare (popmax 0.0103%, amr) (gnomAD).

What do computational predictors say about CCDC137 p.Ala9Glu (c.26C>A)?

AlphaMissense predicts likely benign (score 0.1548) — an in-silico prediction, not a clinical call.

CCDC137 p.Ala9Glu

c.26C>A · VCV4649039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1548	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Pangolin	Δ0.29	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -4.9	GERP -2.4
Regional constraint	o/e 1.10	unconstrained · MANE · 5,934 bp · p 0.06 · regional, not allelic
Overall
CADD	13.63	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 0.0103% Admixed American · 4/38,938 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00211%

Overall 0.00116% 17/1,467,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0103%	9,735
European (non-Finnish)	0.00117%	85,768

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: CCDC137
Protein: p.Ala9Glu
Coding: c.26C>A
MANE Select: NM_199287
Type: single nucleotide variant
Location: chr17:81666792 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94
Residue 9: the 'disordered' region

Full CCDC137 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC137 p.Ala9Val Uncertain significance ★ ⚠ same residue
CCDC137 p.Arg247Cys Uncertain significance ★★ ⚠ same type
CCDC137 p.Ala144Thr Uncertain significance ★ ⚠ same type
CCDC137 p.Ala261Val Uncertain significance ★ ⚠ same type
CCDC137 p.Ala2Ser Uncertain significance ★ ⚠ same type
CCDC137 p.Ala2Val Uncertain significance ★ ⚠ same type
CCDC137 p.Arg12Ser Uncertain significance ★ ⚠ same type
CCDC137 p.Arg146Gln 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/ccdc137-p-ala9glu (accessed [today's date]).

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