Is CCPG1 p.Leu221Phe (c.661C>T) pathogenic?

CCPG1 p.Leu221Phe (c.661C>T) is classified Uncertain significance in CCPG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: ambiguous (0.4981); Very rare (popmax 0.005%, amr).

How common is CCPG1 p.Leu221Phe (c.661C>T) in the general population?

CCPG1 p.Leu221Phe (c.661C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CCPG1 p.Leu221Phe (c.661C>T)?

AlphaMissense predicts ambiguous (score 0.4981) — an in-silico prediction, not a clinical call.

CCPG1 p.Leu221Phe

c.661C>T · VCV3487543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4981	ambiguous
REVEL	0.162	moderately benign-leaning
SaProt	LLR -7.56	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 7.6	GERP 3.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 26 kb · p 0.52 · regional, not allelic
Overall
CADD	25.6	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 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000821% 12/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0048%	20,835
South Asian	0.0011%	91,082
European (non-Finnish)	0.000424%	235,990

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: CCPG1
Protein: p.Leu221Phe
Coding: c.661C>T
MANE Select: NM_001204450
Type: single nucleotide variant
Location: chr15:55371838 (GRCh38)
Gene constraint: LOEUF 0.777 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.96 · 1 PDB
Residue 221: the 'interaction with mcf2l and src' region

Full CCPG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PIGB p.Ile537Met Pathogenic/Likely pathogenic ★★ ⚠ same type
PIGB p.Lys551Thr Benign ★★ same type
PIGB p.Ser509= Benign ★★ same type
CCPG1 p.Ala576Val Uncertain significance ★ ⚠ same type
CCPG1 p.Ala75Thr Uncertain significance ★ ⚠ same type
CCPG1 p.Arg179His Uncertain significance ★ ⚠ same type
CCPG1 p.Arg193Gln Uncertain significance ★ ⚠ same type
CCPG1 p.Arg193Trp 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/ccpg1-p-leu221phe (accessed [today's date]).

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