Is ALAS2 p.Pro425Ser (c.1273C>T) pathogenic?

ALAS2 p.Pro425Ser (c.1273C>T) is classified Uncertain significance in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.8765); Very rare (popmax 0.00439%, amr).

How common is ALAS2 p.Pro425Ser (c.1273C>T) in the general population?

ALAS2 p.Pro425Ser (c.1273C>T) is very rare (popmax 0.00439%, amr) (gnomAD).

What do computational predictors say about ALAS2 p.Pro425Ser (c.1273C>T)?

AlphaMissense predicts likely pathogenic (score 0.8765) — an in-silico prediction, not a clinical call.

ALAS2 p.Pro425Ser

c.1273C>T · rs1350671858 · VCV3253016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8765	likely pathogenic
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -12.50	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	27.5	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 0.00439% Admixed American · 2/45,604 alleles

Filtering AF 0.000727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000272%

Overall 0.000331% 4/1,207,135 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00439%	22,802
European (non-Finnish)	0.000224%	446,768

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: ALAS2
Protein: p.Pro425Ser
Coding: c.1273C>T
MANE Select: NM_000032
dbSNP: rs1350671858
Type: single nucleotide variant
Location: chrX:55014911 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 425: an α-helix

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

Similar variants

ALAS2 p.Pro425Leu Uncertain significance ★ ⚠ same residue
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

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-pro425ser (accessed [today's date]).

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