Is CERS5 p.Trp199Ser (c.596G>C) pathogenic?

CERS5 p.Trp199Ser (c.596G>C) is classified Uncertain significance in CERS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.1593); Very rare (popmax 0.00134%, afr).

How common is CERS5 p.Trp199Ser (c.596G>C) in the general population?

CERS5 p.Trp199Ser (c.596G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CERS5 p.Trp199Ser (c.596G>C)?

AlphaMissense predicts likely benign (score 0.1593) — an in-silico prediction, not a clinical call.

CERS5 p.Trp199Ser

c.596G>C · rs775033866 · VCV3143179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1593	likely benign
REVEL	0.659	pathogenic-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 33 kb · p 0.004 · regional, not allelic
Overall
CADD	25.6	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 0.00134% African / African-American · 1/74,726 alleles

Overall 0.000124% 2/1,609,774 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,726
European (non-Finnish)	8.5e-05%	1,176,964

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: CERS5
Protein: p.Trp199Ser
Coding: c.596G>C
MANE Select: NM_147190
dbSNP: rs775033866
Type: single nucleotide variant
Location: chr12:50137768 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91
Residue 199: the tlc domain

Full CERS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS5 p.Ala278Val Uncertain significance ★ ⚠ same type
CERS5 p.Ala2Thr Uncertain significance ★ ⚠ same type
CERS5 p.Ala338Ser Uncertain significance ★ ⚠ same type
CERS5 p.Ala377Thr Uncertain significance ★ ⚠ same type
CERS5 p.Arg127His Uncertain significance ★ ⚠ same type
CERS5 p.Arg238Gln Uncertain significance ★ ⚠ same type
CERS5 p.Arg267Gln Uncertain significance ★ ⚠ same type
CERS5 p.Arg284Gln 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/cers5-p-trp199ser (accessed [today's date]).

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