Is CCDC8 p.Leu538Pro (c.1613T>C) pathogenic?

CCDC8 p.Leu538Pro (c.1613T>C) is classified Uncertain significance in CCDC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-12). AlphaMissense: likely benign (0.3275); Ultra-rare (popmax 0.0164%, mid).

How common is CCDC8 p.Leu538Pro (c.1613T>C) in the general population?

CCDC8 p.Leu538Pro (c.1613T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCDC8 p.Leu538Pro (c.1613T>C)?

AlphaMissense predicts likely benign (score 0.3275) — an in-silico prediction, not a clinical call.

CCDC8 p.Leu538Pro

c.1613T>C · VCV4887282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3275 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3275	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -5.51	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 5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	22.5	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00136% 22/1,613,826 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0032%	31,239
Admixed American	0.00167%	59,986
European (non-Finnish)	0.00153%	65,554

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: CCDC8
Protein: p.Leu538Pro
Coding: c.1613T>C
MANE Select: NM_032040
Type: single nucleotide variant
Location: chr19:46411198 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 46.83 · 1 PDB

Full CCDC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC8 p.Leu538= Likely benign ★ same residue
CCDC8 p.Ala217Thr Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala293Thr Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala393Val Uncertain significance ★★ ⚠ same type
CCDC8 p.Ala527Val Uncertain significance ★★ ⚠ same type
CCDC8 p.Arg15Gln Uncertain significance ★★ ⚠ same type
CCDC8 p.Arg225Gly Uncertain significance ★★ ⚠ same type
CCDC8 p.Arg277His 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/ccdc8-p-leu538pro (accessed [today's date]).

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