Is ALAS2 p.Phe393Ser (c.1178T>C) pathogenic?

ALAS2 p.Phe393Ser (c.1178T>C) is classified Uncertain significance in ALAS2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9687); Absent from gnomAD v4.1; Associated with X-linked erythropoietic protoporphyria.

What condition is associated with ALAS2 p.Phe393Ser (c.1178T>C)?

ALAS2 p.Phe393Ser (c.1178T>C) is associated with X-linked erythropoietic protoporphyria, X-linked sideroblastic anemia 1 (ClinVar).

How common is ALAS2 p.Phe393Ser (c.1178T>C) in the general population?

ALAS2 p.Phe393Ser (c.1178T>C) is absent from gnomAD v4.1 (gnomAD).

How is X-linked erythropoietic protoporphyria inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALAS2 p.Phe393Ser (c.1178T>C)?

AlphaMissense predicts likely pathogenic (score 0.9687) — an in-silico prediction, not a clinical call.

ALAS2 p.Phe393Ser

c.1178T>C · VCV3382870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9687 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked erythropoietic protoporphyria

Computational evidence

Protein change
AlphaMissense	0.9687	likely pathogenic
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 8,973 bp · p 5.5e-15 · regional, not allelic
Overall
CADD	27.0	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: ALAS2
Protein: p.Phe393Ser
Coding: c.1178T>C
MANE Select: NM_000032
Type: single nucleotide variant
Location: chrX:55015006 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB

Full ALAS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked erythropoietic protoporphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked sideroblastic anemia 1

For X-linked erythropoietic protoporphyria (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood

Similar variants

ALAS2 p.Arg411Cys Pathogenic ★★ same condition
ALAS2 p.Arg452Cys Pathogenic ★★ ⚠ same condition
ALAS2 p.Ala336Asp Uncertain significance ★★ ⚠ same condition
ALAS2 p.Cys471Arg Uncertain significance ★★ ⚠ same condition
ALAS2 p.Leu353Val Uncertain significance ★★ ⚠ same condition
ALAS2 c.824-15C>T Benign ★★ same condition
ALAS2 c.-15-1790G>A Benign/Likely benign ★★ same condition
ALAS2 c.*124C>T Benign/Likely 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/alas2-p-phe393ser (accessed [today's date]).

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