Is CCER1 p.Phe378Cys (c.1133T>G) pathogenic?

CCER1 p.Phe378Cys (c.1133T>G) is classified Uncertain significance in CCER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.6129); Ultra-rare (popmax 0.0165%, mid).

How common is CCER1 p.Phe378Cys (c.1133T>G) in the general population?

CCER1 p.Phe378Cys (c.1133T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CCER1 p.Phe378Cys (c.1133T>G)?

AlphaMissense predicts likely pathogenic (score 0.6129) — an in-silico prediction, not a clinical call.

CCER1 p.Phe378Cys

c.1133T>G · VCV4221856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6129	likely pathogenic · top 7% in CCER1
REVEL	0.205	benign-leaning
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.73, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,217 bp · p 0.034 · regional, not allelic
Overall
CADD	18.68	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000137% 2/1,461,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00133%	75,000

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: CCER1
Protein: p.Phe378Cys
Coding: c.1133T>G
MANE Select: NM_152638
Type: single nucleotide variant
Location: chr12:90953610 (GRCh38)
Gene constraint: LOEUF 1.814 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 50.34
Residue 378: a UniProt-annotated variant site (found in a patient with non-obstructive azoospermia; uncertain significance)

Full CCER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCER1 p.Ala164Glu Uncertain significance ★ ⚠ same type
CCER1 p.Ala225Thr Uncertain significance ★ ⚠ same type
CCER1 p.Ala27Val Uncertain significance ★ ⚠ same type
CCER1 p.Ala297Thr Uncertain significance ★ ⚠ same type
CCER1 p.Arg142Gly Uncertain significance ★ ⚠ same type
CCER1 p.Arg145His Uncertain significance ★ ⚠ same type
CCER1 p.Arg155Leu Uncertain significance ★ ⚠ same type
CCER1 p.Asn195Asp 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/ccer1-p-phe378cys (accessed [today's date]).

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