Is CERS2 p.Ser196Arg (c.586A>C) pathogenic?

CERS2 p.Ser196Arg (c.586A>C) is classified Uncertain significance in CERS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-28). AlphaMissense: likely pathogenic (0.5737); Ultra-rare (popmax 0.0526%, nfe).

How common is CERS2 p.Ser196Arg (c.586A>C) in the general population?

CERS2 p.Ser196Arg (c.586A>C) is ultra-rare (popmax 0.0526%, nfe) (gnomAD).

What do computational predictors say about CERS2 p.Ser196Arg (c.586A>C)?

AlphaMissense predicts likely pathogenic (score 0.5737) — an in-silico prediction, not a clinical call.

CERS2 p.Ser196Arg

c.586A>C · rs199945675 · VCV2403183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0526%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5737	likely pathogenic
REVEL	0.598	indeterminate
SaProt	LLR -13.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.25	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,991 bp · p 3.1e-05 · regional, not allelic
Overall
CADD	23.2	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 0.0526% European (non-Finnish) · 616/1,170,138 alleles

Filtering AF 0.0491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.0407% 653/1,603,236 alleles · ultra-rare exomes 616/1,450,944 · genomes 37/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0526%	1,900
Remaining individualsnot grpmax-eligible	0.0515%	1,942
African / African-American	0.00668%	14,962

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: CERS2
Protein: p.Ser196Arg
Coding: c.586A>C
MANE Select: NM_022075
dbSNP: rs199945675
Type: single nucleotide variant
Location: chr1:150967418 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 87.31
Residue 196: the tlc domain

Full CERS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS2 p.Ala152= Benign ★★ same type
CERS2 p.Ser199= Benign ★★ same type
CERS2 p.Tyr254= Benign ★★ same type
CERS2 p.Ala23Ser Uncertain significance ★ ⚠ same type
CERS2 p.Ala23Val Uncertain significance ★ ⚠ same type
CERS2 p.Ala34Thr Uncertain significance ★ same type
CERS2 p.Ala46Gly Uncertain significance ★ ⚠ same type
CERS2 p.Arg105Leu 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/cers2-p-ser196arg (accessed [today's date]).

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