Is ALAS2 p.Val142Ala (c.425T>C) pathogenic?

ALAS2 p.Val142Ala (c.425T>C) is classified Uncertain significance in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-18). AlphaMissense: likely benign (0.0678); Very rare (popmax 9.15e-05%).

How common is ALAS2 p.Val142Ala (c.425T>C) in the general population?

ALAS2 p.Val142Ala (c.425T>C) is very rare (popmax 9.15e-05%) (gnomAD).

What do computational predictors say about ALAS2 p.Val142Ala (c.425T>C)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

ALAS2 p.Val142Ala

c.425T>C · rs2519587879 · VCV2697006

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.15e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -4.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.65	GERP -3.7, phastCons 0.002
Regional constraint	o/e 0.52	unconstrained · MANE · 8,973 bp · p 5.5e-15 · regional, not allelic
Overall
CADD	4.678	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 9.15e-05%

Overall 9.15e-05% 1/1,093,365 alleles · very rare

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.Val142Ala
Coding: c.425T>C
MANE Select: NM_000032
dbSNP: rs2519587879
Type: single nucleotide variant
Location: chrX:55021265 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB

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-val142ala (accessed [today's date]).

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