Is CERS1 p.Arg197Trp (c.589C>T) pathogenic?

CERS1 p.Arg197Trp (c.589C>T) is classified Uncertain significance in CERS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.8702); Very rare (popmax 0.0022%, sas).

How common is CERS1 p.Arg197Trp (c.589C>T) in the general population?

CERS1 p.Arg197Trp (c.589C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CERS1 p.Arg197Trp (c.589C>T)?

AlphaMissense predicts likely pathogenic (score 0.8702) — an in-silico prediction, not a clinical call.

CERS1 p.Arg197Trp

c.589C>T · VCV4226648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8702	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -12.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 25 kb · p 1 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/90,804 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000559% 9/1,611,450 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,402
Remaining individualsnot grpmax-eligible	0.0016%	62,358
European (non-Finnish)	0.000509%	196,426

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.Arg197Trp
Coding: c.589C>T
MANE Select: NM_021267
Type: single nucleotide variant
Location: chr19:18884088 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 88.95
Residue 197: 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

CERS1 p.Arg197Gln Uncertain significance ★ ⚠ same residue
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

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-arg197trp (accessed [today's date]).

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