Is CCDC138 p.Leu592Phe (c.1774C>T) pathogenic?

CCDC138 p.Leu592Phe (c.1774C>T) is classified Uncertain significance in CCDC138 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: ambiguous (0.4882); Absent from gnomAD v4.1.

How common is CCDC138 p.Leu592Phe (c.1774C>T) in the general population?

CCDC138 p.Leu592Phe (c.1774C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCDC138 p.Leu592Phe (c.1774C>T)?

AlphaMissense predicts ambiguous (score 0.4882) — an in-silico prediction, not a clinical call.

CCDC138 p.Leu592Phe

c.1774C>T · rs2470480693 · VCV2235106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4882 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4882	ambiguous
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 89 kb · p 0.038 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCDC138
Protein: p.Leu592Phe
Coding: c.1774C>T
MANE Select: NM_144978
dbSNP: rs2470480693
Type: single nucleotide variant
Location: chr2:108873531 (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-leu592phe (accessed [today's date]).

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