Is CERS6 p.Cys380Arg (c.1138T>C) pathogenic?

CERS6 p.Cys380Arg (c.1138T>C) is classified Uncertain significance in CERS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0911); Very rare (popmax 0.00267%, afr).

How common is CERS6 p.Cys380Arg (c.1138T>C) in the general population?

CERS6 p.Cys380Arg (c.1138T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CERS6 p.Cys380Arg (c.1138T>C)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

CERS6 p.Cys380Arg

c.1138T>C · VCV4001306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -4.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 313 kb · p 0.015 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,778 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,610,696 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,389
European (non-Finnish)	0.00017%	589,504

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: CERS6
Protein: p.Cys380Arg
Coding: c.1138T>C
MANE Select: NM_203463
Type: single nucleotide variant
Location: chr2:168769645 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI 0.43 (gnomAD)
Structure: AlphaFold pLDDT 87.97 · 3 PDB
Residue 380: the 'disordered' region

Full CERS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS6 p.Ala30Ser Uncertain significance ★ ⚠ same type
CERS6 p.Ala326Val Uncertain significance ★ ⚠ same type
CERS6 p.Ala362Val Uncertain significance ★ ⚠ same type
CERS6 p.Ala6Val Uncertain significance ★ ⚠ same type
CERS6 p.Arg121Cys Uncertain significance ★ ⚠ same type
CERS6 p.Asn10Lys Uncertain significance ★ ⚠ same type
CERS6 p.Asn122Ser Uncertain significance ★ ⚠ same type
CERS6 p.Asn168Lys 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/cers6-p-cys380arg (accessed [today's date]).

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