Is CCDC138 p.Ser80Arg (c.238A>C) pathogenic?

CCDC138 p.Ser80Arg (c.238A>C) is classified Uncertain significance in CCDC138 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.1516); Ultra-rare (popmax 0.012%, nfe).

How common is CCDC138 p.Ser80Arg (c.238A>C) in the general population?

CCDC138 p.Ser80Arg (c.238A>C) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about CCDC138 p.Ser80Arg (c.238A>C)?

AlphaMissense predicts likely benign (score 0.1516) — an in-silico prediction, not a clinical call.

CCDC138 p.Ser80Arg

c.238A>C · rs753008334 · VCV2357169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1516 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1516	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.12	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 0.87	GERP -2.8, phastCons 0.029
Regional constraint	o/e 1.08	unconstrained · MANE · 89 kb · p 0.038 · regional, not allelic
Overall
CADD	8.098	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 0.012% European (non-Finnish) · 142/1,179,980 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0098%

Overall 0.00898% 145/1,613,978 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,310
Remaining individualsnot grpmax-eligible	0.0048%	20,826

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.Ser80Arg
Coding: c.238A>C
MANE Select: NM_144978
dbSNP: rs753008334
Type: single nucleotide variant
Location: chr2:108788938 (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-ser80arg (accessed [today's date]).

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