Is CCDC15 p.Phe640Leu (c.1920T>G) pathogenic?

CCDC15 p.Phe640Leu (c.1920T>G) is classified Uncertain significance in CCDC15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.8088); Very rare (popmax 0.00166%, nfe).

How common is CCDC15 p.Phe640Leu (c.1920T>G) in the general population?

CCDC15 p.Phe640Leu (c.1920T>G) is very rare (popmax 0.00166%, nfe) (gnomAD).

What do computational predictors say about CCDC15 p.Phe640Leu (c.1920T>G)?

AlphaMissense predicts likely pathogenic (score 0.8088) — an in-silico prediction, not a clinical call.

CCDC15 p.Phe640Leu

c.1920T>G · rs759642031 · VCV3138508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00166%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8088	likely pathogenic · top 5% in CCDC15
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.32	GERP -3.1
Regional constraint	o/e 1.01	unconstrained · MANE · 86 kb · p 0.73 · regional, not allelic
Overall
CADD	15.96	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 0.00166% European (non-Finnish) · 19/1,145,690 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000855%

Overall 0.0116% 181/1,563,904 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.496%	201
Remaining individualsnot grpmax-eligible	0.0348%	2,874
European (non-Finnish)grpmax	0.00166%	60,299

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCDC15
Protein: p.Phe640Leu
Coding: c.1920T>G
MANE Select: NM_025004
dbSNP: rs759642031
Type: single nucleotide variant
Location: chr11:124991472 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.02

Full CCDC15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC15 p.Arg181Cys Uncertain significance ★★ ⚠ same type
CCDC15 p.Pro10= Benign ★★ same type
CCDC15 p.Ala110Thr Uncertain significance ★ ⚠ same type
CCDC15 p.Ala140Val Uncertain significance ★ ⚠ same type
CCDC15 p.Ala19Thr Uncertain significance ★ ⚠ same type
CCDC15 p.Ala44Ser Uncertain significance ★ ⚠ same type
CCDC15 p.Ala44Val Uncertain significance ★ ⚠ same type
CCDC15 p.Ala6Thr 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/ccdc15-p-phe640leu (accessed [today's date]).

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