Is ALAS2 p.Ser347Phe (c.1040C>T) pathogenic?

ALAS2 p.Ser347Phe (c.1040C>T) is classified Uncertain significance in ALAS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.9672); Absent from gnomAD v4.1.

How common is ALAS2 p.Ser347Phe (c.1040C>T) in the general population?

ALAS2 p.Ser347Phe (c.1040C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALAS2 p.Ser347Phe (c.1040C>T)?

AlphaMissense predicts likely pathogenic (score 0.9672) — an in-silico prediction, not a clinical call.

ALAS2 p.Ser347Phe

c.1040C>T · rs2146717399 · VCV1328685

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9672 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9672	likely pathogenic
REVEL	0.735	pathogenic-leaning
SaProt	LLR -12.42	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 1.9, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 8,973 bp · p 5.5e-15 · regional, not allelic
Overall
CADD	27.2	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: ALAS2
Protein: p.Ser347Phe
Coding: c.1040C>T
MANE Select: NM_000032
dbSNP: rs2146717399
Type: single nucleotide variant
Location: chrX:55015706 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 347: an α-helix

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

Similar variants

ALAS2 p.Arg170Cys Pathogenic/Likely pathogenic ★★ same type
ALAS2 p.Arg411Cys Pathogenic ★★ same type
ALAS2 p.Arg452Cys Pathogenic ★★ same type
ALAS2 p.Arg452His Pathogenic ★★ ⚠ same type
ALAS2 p.Arg452Ser Pathogenic ★★ ⚠ same type
ALAS2 c.1168+4A>C Uncertain significance ★★ same type
ALAS2 p.Ala282Thr Uncertain significance ★★ ⚠ same type
ALAS2 p.Ala336Asp 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/alas2-p-ser347phe (accessed [today's date]).

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