Is CCDC8 p.Asp381Asn (c.1141G>A) pathogenic?

CCDC8 p.Asp381Asn (c.1141G>A) is classified Benign/Likely benign in CCDC8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.0765); Common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CCDC8 p.Asp381Asn (c.1141G>A)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

CCDC8 p.Asp381Asn

Q: How common is CCDC8 p.Asp381Asn (c.1141G>A) in the general population?

CCDC8 p.Asp381Asn (c.1141G>A) is common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1141G>A · rs75175362 · VCV262003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -9.55	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 -0.63	GERP 0.83
Regional constraint	o/e 1.02	unconstrained · MANE · 1,613 bp · p 0.66 · regional, not allelic
Overall
CADD	3.558	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

Grpmax group 16% East Asian · 6,989/43,550 alleles

Filtering AF 15.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.6%

Overall 5.6% 88,762/1,584,976 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	16%	6
Finnishnot grpmax-eligible	10.3%	10
Amishnot grpmax-eligible	8.66%	12
Admixed American	8.08%	12
South Asian	7.7%	13
Remaining individualsnot grpmax-eligible	5.81%	17
European (non-Finnish)	4.91%	20
Ashkenazi Jewishnot grpmax-eligible	3.25%	31
African / African-American	2.88%	35
Middle Eastern	2.07%	48

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.Asp381Asn
Coding: c.1141G>A
MANE Select: NM_032040
dbSNP: rs75175362
Type: single nucleotide variant
Location: chr19:46411670 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 46.83 · 1 PDB
Residue 381: the 'disordered' region

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

Similar variants

CCDC8 p.Asp381His Uncertain significance ★ ⚠ 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-asp381asn (accessed [today's date]).

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