Is CCDC137 p.Arg263Ser (c.789A>C) pathogenic?

CCDC137 p.Arg263Ser (c.789A>C) is classified Uncertain significance in CCDC137 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.8398); Ultra-rare (popmax 0.0308%, afr).

How common is CCDC137 p.Arg263Ser (c.789A>C) in the general population?

CCDC137 p.Arg263Ser (c.789A>C) is ultra-rare (popmax 0.0308%, afr) (gnomAD).

What do computational predictors say about CCDC137 p.Arg263Ser (c.789A>C)?

AlphaMissense predicts likely pathogenic (score 0.8398) — an in-silico prediction, not a clinical call.

CCDC137 p.Arg263Ser

c.789A>C · VCV3486003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8398 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8398	likely pathogenic · top 3% in CCDC137
REVEL	0.466	indeterminate
SaProt	LLR -13.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.059	GERP -4, phastCons 0.085
Regional constraint	o/e 1.10	unconstrained · MANE · 5,934 bp · p 0.06 · regional, not allelic
Overall
CADD	16.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0308% African / African-American · 23/74,722 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00163% 26/1,598,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0308%	3,249
Remaining individualsnot grpmax-eligible	0.00323%	30,938
Admixed American	0.00174%	57,538

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.Arg263Ser
Coding: c.789A>C
MANE Select: NM_199287
Type: single nucleotide variant
Location: chr17:81672623 (GRCh38)
Gene constraint: LOEUF 1.308 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.94

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

Similar variants

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.Ala9Glu Uncertain significance ★ ⚠ same type
CCDC137 p.Ala9Val Uncertain significance ★ ⚠ same type
CCDC137 p.Arg12Ser 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-arg263ser (accessed [today's date]).

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