Is CCDC138 p.Ser27Arg (c.81C>G) pathogenic?

CCDC138 p.Ser27Arg (c.81C>G) is classified Uncertain significance in CCDC138 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.1488); Very rare (popmax 0.00202%, amr).

How common is CCDC138 p.Ser27Arg (c.81C>G) in the general population?

CCDC138 p.Ser27Arg (c.81C>G) is very rare (popmax 0.00202%, amr) (gnomAD).

What do computational predictors say about CCDC138 p.Ser27Arg (c.81C>G)?

AlphaMissense predicts likely benign (score 0.1488) — an in-silico prediction, not a clinical call.

CCDC138 p.Ser27Arg

c.81C>G · VCV3486008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00202%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1488	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -7.39	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 0.042	GERP -1.4
Regional constraint	o/e 1.08	unconstrained · MANE · 89 kb · p 0.038 · regional, not allelic
Overall
CADD	13.06	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 0.00202% Admixed American · 1/49,542 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000359% 5/1,394,000 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00202%	49,542
Remaining individualsnot grpmax-eligible	0.00168%	59,626
European (non-Finnish)	0.000261%	383,052

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: CCDC138
Protein: p.Ser27Arg
Coding: c.81C>G
MANE Select: NM_144978
Type: single nucleotide variant
Location: chr2:108786903 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.25

Full CCDC138 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC138 p.Ala133Val Uncertain significance ★ ⚠ same type
CCDC138 p.Ala166Thr Uncertain significance ★ ⚠ same type
CCDC138 p.Ala340Thr Uncertain significance ★ ⚠ same type
CCDC138 p.Ala482Thr Uncertain significance ★ ⚠ same type
CCDC138 p.Ala663Thr Uncertain significance ★ ⚠ same type
CCDC138 p.Arg142Ser Uncertain significance ★ ⚠ same type
CCDC138 p.Arg170Trp Uncertain significance ★ ⚠ same type
CCDC138 p.Arg210His 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/ccdc138-p-ser27arg (accessed [today's date]).

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