Is CERS4 p.Arg66Trp (c.196C>T) pathogenic?

CERS4 p.Arg66Trp (c.196C>T) is classified Uncertain significance in CERS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.1158); Ultra-rare (popmax 0.0174%, afr).

How common is CERS4 p.Arg66Trp (c.196C>T) in the general population?

CERS4 p.Arg66Trp (c.196C>T) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about CERS4 p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

CERS4 p.Arg66Trp

c.196C>T · VCV3491043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -0.89, phastCons 0.049
Regional constraint	o/e 1.13	unconstrained · MANE · 11 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.2	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 0.0174% African / African-American · 13/74,898 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00297% 48/1,613,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
East Asian	0.0134%	7,479
South Asian	0.00988%	10,118
Admixed American	0.005%	19,989
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00127%	78,664

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: CERS4
Protein: p.Arg66Trp
Coding: c.196C>T
MANE Select: NM_024552
Type: single nucleotide variant
Location: chr19:8254521 (GRCh38)
Gene constraint: LOEUF 1.472 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.92

Full CERS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS4 p.Arg66Gln Uncertain significance ★ ⚠ same residue
CERS4 p.Arg66Pro Uncertain significance ★ same residue
CERS4 p.Ala82Thr Likely benign ★★ same type
CERS4 p.Leu194= Benign ★★ same type
CERS4 p.Ala162Val Uncertain significance ★ ⚠ same type
CERS4 p.Ala373Thr Uncertain significance ★ ⚠ same type
CERS4 p.Ala46Val Uncertain significance ★ ⚠ same type
CERS4 p.Arg116Gln 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/cers4-p-arg66trp (accessed [today's date]).

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