Is ALAS2 c.304+2T>C pathogenic?

ALAS2 c.304+2T>C is classified Likely pathogenic in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). Absent from gnomAD v4.1; Associated with X-linked erythropoietic protoporphyria.

What condition is associated with ALAS2 c.304+2T>C?

ALAS2 c.304+2T>C is associated with X-linked erythropoietic protoporphyria (ClinVar).

How common is ALAS2 c.304+2T>C in the general population?

ALAS2 c.304+2T>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.

ALAS2 c.304+2T>C

VCV3341449

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

X-linked erythropoietic protoporphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.79	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Non-coding constraint	—	not assessed · autosomes only, so chrX has no window · absence ≠ unconstrained
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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
Coding: c.304+2T>C
MANE Select: NM_000032
Type: single nucleotide variant
Location: chrX:55024716 (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

For X-linked erythropoietic protoporphyria (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood

Similar variants

ALAS2 p.Leu353Val Uncertain significance ★★ ⚠ same condition
ALAS2 c.-15-1790G>A Benign/Likely benign ★★ same condition
ALAS2 p.Pro520Leu Benign/Likely benign ★★ same condition
ALAS2 c.1168+19C>A Uncertain significance ★ same condition
ALAS2 c.304+1G>C Uncertain significance ★ same condition
ALAS2 p.Ala221Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
ALAS2 p.Arg511Leu Uncertain significance ★ ⚠ same condition
ALAS2 p.His523Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-c-304-plus-2t-c (accessed [today's date]).

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