Is CCDC38 p.Phe77Leu (c.231C>A) pathogenic?

CCDC38 p.Phe77Leu (c.231C>A) is classified Uncertain significance in CCDC38 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.5155); Ultra-rare (popmax 0.0187%, afr).

How common is CCDC38 p.Phe77Leu (c.231C>A) in the general population?

CCDC38 p.Phe77Leu (c.231C>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about CCDC38 p.Phe77Leu (c.231C>A)?

AlphaMissense predicts ambiguous (score 0.5155) — an in-silico prediction, not a clinical call.

CCDC38 p.Phe77Leu

c.231C>A · VCV4221212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5155 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5155	ambiguous
REVEL	0.028	moderately benign-leaning
SaProt	LLR -5.11	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 0.52	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 69 kb · p 0.61 · regional, not allelic
Overall
CADD	2.199	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 0.0187% African / African-American · 14/74,706 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00907%

Overall 0.00112% 18/1,610,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,336
Admixed American	0.00512%	19,528
Remaining individualsnot grpmax-eligible	0.00161%	62,266

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: CCDC38
Protein: p.Phe77Leu
Coding: c.231C>A
MANE Select: NM_182496
Type: single nucleotide variant
Location: chr12:95917202 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.84

Full CCDC38 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC38 p.Ala125Ser Uncertain significance ★ ⚠ same type
CCDC38 p.Ala175Ser Uncertain significance ★ ⚠ same type
CCDC38 p.Ala175Thr Uncertain significance ★ ⚠ same type
CCDC38 p.Ala407Val Uncertain significance ★ ⚠ same type
CCDC38 p.Ala425Val Uncertain significance ★ ⚠ same type
CCDC38 p.Ala76Pro Uncertain significance ★ ⚠ same type
CCDC38 p.Arg107Met Uncertain significance ★ ⚠ same type
CCDC38 p.Arg145Gln 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/ccdc38-p-phe77leu (accessed [today's date]).

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