Is CERS3 p.Ala46Asp (c.137C>A) pathogenic?

CERS3 p.Ala46Asp (c.137C>A) is classified Uncertain significance in CERS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.9641); Very rare (popmax 0.0011%, sas); Associated with Ichthyosis and erythrokeratoderma.

What condition is associated with CERS3 p.Ala46Asp (c.137C>A)?

CERS3 p.Ala46Asp (c.137C>A) is associated with Ichthyosis and erythrokeratoderma (ClinVar).

How common is CERS3 p.Ala46Asp (c.137C>A) in the general population?

CERS3 p.Ala46Asp (c.137C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CERS3 p.Ala46Asp (c.137C>A)?

AlphaMissense predicts likely pathogenic (score 0.9641) — an in-silico prediction, not a clinical call.

CERS3 p.Ala46Asp

c.137C>A · VCV4538571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ichthyosis and erythrokeratoderma

Computational evidence

Protein change
AlphaMissense	0.9641	likely pathogenic · top 3% in CERS3
REVEL	0.729	pathogenic-leaning
SaProt	LLR -15.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.93, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	27.9	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 0.0011% South Asian · 1/91,074 alleles

Overall 0.000137% 2/1,461,520 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	8.48e-05%	1,179,732

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: CERS3
Protein: p.Ala46Asp
Coding: c.137C>A
MANE Select: NM_001378789
Type: single nucleotide variant
Location: chr15:100501713 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52

Full CERS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ichthyosis and erythrokeratoderma

Similar variants

CERS3 c.1000-1G>C Likely pathogenic ★ same condition
CERS3 c.465+1G>A Likely pathogenic ★ same condition
CERS3 p.Gln336Ter Likely pathogenic ★ same condition
CERS3 p.Gly149Arg Likely pathogenic ★ same condition
CERS3 c.173+9T>C Likely benign same condition
CERS3 c.466-1G>T Likely pathogenic ★★ same type
CERS3 p.Arg75Ter Likely pathogenic ★★ same type
CERS3 p.Arg275Cys 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/cers3-p-ala46asp (accessed [today's date]).

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