Is CERS3 p.His211Asp (c.631C>G) pathogenic?

CERS3 p.His211Asp (c.631C>G) is classified Uncertain significance in CERS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-22). AlphaMissense: likely pathogenic (0.9954); Absent from gnomAD v4.1; Associated with autosomal recessive congenital ichthyosis 9.

What condition is associated with CERS3 p.His211Asp (c.631C>G)?

CERS3 p.His211Asp (c.631C>G) is associated with autosomal recessive congenital ichthyosis 9 (ClinVar).

How common is CERS3 p.His211Asp (c.631C>G) in the general population?

CERS3 p.His211Asp (c.631C>G) is absent from gnomAD v4.1 (gnomAD).

How is Congenital ichthyosiform erythroderma inherited?

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

What do computational predictors say about CERS3 p.His211Asp (c.631C>G)?

AlphaMissense predicts likely pathogenic (score 0.9954) — an in-silico prediction, not a clinical call.

CERS3 p.His211Asp

c.631C>G · VCV3779053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9954 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive congenital ichthyosis 9

Computational evidence

Protein change
AlphaMissense	0.9954	likely pathogenic · top 1% in CERS3
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -12.55	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 99 kb · p 0.65 · regional, not allelic
Overall
CADD	29.7	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

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: CERS3
Protein: p.His211Asp
Coding: c.631C>G
MANE Select: NM_001378789
Type: single nucleotide variant
Location: chr15:100473031 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52
Residue 211: the tlc domain

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

Disease context

autosomal recessive congenital ichthyosis 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital ichthyosiform erythroderma (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Spain)

Similar variants

CERS3 p.His211Leu Uncertain significance ★ ⚠ same residue
CERS3 c.466-1G>T Likely pathogenic ★★ same condition
CERS3 p.Arg75Ter Likely pathogenic ★★ same condition
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same condition
CERS3 c.845+53C>T Benign ★★ same condition
CERS3 c.999+60G>A Benign ★★ same condition
CERS3 c.*75C>A Benign ★★ same condition
CERS3 p.Arg370Gly Benign ★★ 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/cers3-p-his211asp (accessed [today's date]).

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