Is CERS1 p.Phe225Val (c.673T>G) pathogenic?

CERS1 p.Phe225Val (c.673T>G) is classified Uncertain significance in CERS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: ambiguous (0.4496); Very rare (popmax 0.00026%, nfe).

How common is CERS1 p.Phe225Val (c.673T>G) in the general population?

CERS1 p.Phe225Val (c.673T>G) is very rare (popmax 0.00026%, nfe) (gnomAD).

What do computational predictors say about CERS1 p.Phe225Val (c.673T>G)?

AlphaMissense predicts ambiguous (score 0.4496) — an in-silico prediction, not a clinical call.

CERS1 p.Phe225Val

c.673T>G · VCV4226652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4496 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00026%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4496	ambiguous
REVEL	0.363	indeterminate
SaProt	LLR -5.47	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	23.4	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 0.00026% European (non-Finnish) · 3/1,156,070 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000191% 3/1,567,196 alleles · very rare

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: CERS1
Protein: p.Phe225Val
Coding: c.673T>G
MANE Select: NM_021267
Type: single nucleotide variant
Location: chr19:18880353 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 225: a UniProt-annotated variant site (in epm8); the tlc domain

Full CERS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GDF1 p.Cys227Ter Pathogenic/Likely pathogenic ★★ same type
GDF1 p.Met364Thr Pathogenic/Likely pathogenic ★★ same type
CERS1 p.Ala117Ser Uncertain significance ★★ ⚠ same type
CERS1 p.Ala165Thr Uncertain significance ★★ ⚠ same type
CERS1 p.Ala266Val Uncertain significance ★★ ⚠ same type
CERS1 p.Ala286Val Uncertain significance ★★ ⚠ same type
CERS1 p.Ala304Val Uncertain significance ★★ ⚠ same type
CERS1 p.Ala45Pro 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/cers1-p-phe225val (accessed [today's date]).

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