Is CCER1 p.Pro136Ser (c.406C>T) pathogenic?

CCER1 p.Pro136Ser (c.406C>T) is classified Uncertain significance in CCER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1666); Ultra-rare (popmax 0.0267%, afr).

How common is CCER1 p.Pro136Ser (c.406C>T) in the general population?

CCER1 p.Pro136Ser (c.406C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about CCER1 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.1666) — an in-silico prediction, not a clinical call.

CCER1 p.Pro136Ser

c.406C>T · VCV4221847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1666	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.96	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 4.2	GERP -0.76, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,217 bp · p 0.034 · regional, not allelic
Overall
CADD	16.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/75,044 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00348% 56/1,607,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.00801%	12,480
Admixed American	0.00334%	29,953
European (non-Finnish)	0.00237%	42,124
South Asian	0.0011%	90,998

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.Pro136Ser
Coding: c.406C>T
MANE Select: NM_152638
Type: single nucleotide variant
Location: chr12:90954337 (GRCh38)
Gene constraint: LOEUF 1.814 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 50.34
Residue 136: 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-pro136ser (accessed [today's date]).

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