Is ACER3 p.Ser235Arg (c.703A>C) pathogenic?

ACER3 p.Ser235Arg (c.703A>C) is classified Pathogenic in ACER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-11). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1; Associated with alkaline ceramidase 3 deficiency.

What condition is associated with ACER3 p.Ser235Arg (c.703A>C)?

ACER3 p.Ser235Arg (c.703A>C) is associated with alkaline ceramidase 3 deficiency (ClinVar).

How common is ACER3 p.Ser235Arg (c.703A>C) in the general population?

ACER3 p.Ser235Arg (c.703A>C) is absent from gnomAD v4.1 (gnomAD).

How is Alkaline ceramidase 3 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ACER3 p.Ser235Arg (c.703A>C)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

ACER3 p.Ser235Arg

c.703A>C · VCV3336618

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alkaline ceramidase 3 deficiency

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic ✓ concordant with ClinVar · top 8% in ACER3
REVEL	0.221	benign-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Pangolin	Δ0.36	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 159 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACER3
Protein: p.Ser235Arg
Coding: c.703A>C
MANE Select: NM_018367
Type: single nucleotide variant
Location: chr11:77016778 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 93.23 · 2 PDB
Residue 235: an α-helix

Full ACER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

alkaline ceramidase 3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alkaline ceramidase 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

ACER3 p.Arg159Ter Likely pathogenic ★ same condition
ACER3 p.Arg203Ter Pathogenic ★ same condition
ACER3 p.Gly211Cys Pathogenic ★ same condition
ACER3 p.Cys196Tyr Conflicting classifications of pathogenicity ★ ⚠ same condition
ACER3 p.Glu33Gly Uncertain significance ★ ⚠ same condition
ACER3 p.Phe80Leu Uncertain significance ★ ⚠ same condition
ACER3 p.Trp78Arg Uncertain significance ★ same condition
ACER3 p.Trp189Ter Pathogenic same condition

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/acer3-p-ser235arg (accessed [today's date]).

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