Is CER1 p.Ser227Phe (c.680C>T) pathogenic?

CER1 p.Ser227Phe (c.680C>T) is classified Uncertain significance in CER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1401); Ultra-rare (popmax 0.0209%, sas).

How common is CER1 p.Ser227Phe (c.680C>T) in the general population?

CER1 p.Ser227Phe (c.680C>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about CER1 p.Ser227Phe (c.680C>T)?

AlphaMissense predicts likely benign (score 0.1401) — an in-silico prediction, not a clinical call.

CER1 p.Ser227Phe

c.680C>T · VCV4226599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1401	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -9.22	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 0.056	GERP -0.96
Regional constraint	o/e 1.32	unconstrained · MANE · 2,579 bp · p 8.8e-09 · regional, not allelic
Overall
CADD	12.98	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 0.0209% South Asian · 19/91,070 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00171% 25/1,461,864 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,793
European (non-Finnish)	0.000508%	196,672

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: CER1
Protein: p.Ser227Phe
Coding: c.680C>T
Type: single nucleotide variant
Location: chr9:14720214 (GRCh38)

Full CER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CER1 p.Ala198Val Uncertain significance ★ ⚠ same type
CER1 p.Ala199Gly Uncertain significance ★ ⚠ same type
CER1 p.Ala199Val Uncertain significance ★ ⚠ same type
CER1 p.Ala59Thr Uncertain significance ★ ⚠ same type
CER1 p.Arg24Cys Uncertain significance ★ ⚠ same type
CER1 p.Arg24His Uncertain significance ★ ⚠ same type
CER1 p.Arg85Lys Uncertain significance ★ ⚠ same type
CER1 p.Arg92Thr 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/cer1-p-ser227phe (accessed [today's date]).

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