Is ALAS2 p.Ser64Pro (c.190T>C) pathogenic?

ALAS2 p.Ser64Pro (c.190T>C) is classified Conflicting classifications of pathogenicity in ALAS2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0816); Ultra-rare (popmax 0.0192%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALAS2 p.Ser64Pro (c.190T>C)?

ALAS2 p.Ser64Pro (c.190T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ALAS2 p.Ser64Pro (c.190T>C) in the general population?

ALAS2 p.Ser64Pro (c.190T>C) is ultra-rare (popmax 0.0192%, nfe) (gnomAD).

What do computational predictors say about ALAS2 p.Ser64Pro (c.190T>C)?

AlphaMissense predicts likely benign (score 0.0816) — an in-silico prediction, not a clinical call.

ALAS2 p.Ser64Pro

c.190T>C · rs201875716 · VCV214093

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0816	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,159 bp · p 0.19 · regional, not allelic
Overall
CADD	14.15	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

Grpmax group 0.0192% European (non-Finnish) · 172/895,078 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.015% 181/1,209,901 alleles · ultra-rare exomes 163/1,098,008 · genomes 18/111,893 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0192%	5,204
Remaining individualsnot grpmax-eligible	0.0168%	5,950
African / African-American	0.00175%	57,151

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.Ser64Pro
Coding: c.190T>C
MANE Select: NM_000032
dbSNP: rs201875716
Type: single nucleotide variant
Location: chrX:55024832 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALAS2 p.Arg375His Uncertain significance ★★ ⚠ same condition
ALAS2 p.Arg479Trp Uncertain significance ★★ ⚠ same condition
ALAS2 p.Asp308Asn Uncertain significance ★★ ⚠ same condition
ALAS2 p.Cys471Arg Uncertain significance ★★ ⚠ same condition
ALAS2 p.Glu277Lys Uncertain significance ★★ ⚠ same condition
ALAS2 p.Gly80Glu Uncertain significance ★★ ⚠ same condition
ALAS2 p.Leu489Val Uncertain significance ★★ ⚠ same condition
ALAS2 p.Leu547Val Uncertain significance ★★ ⚠ 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-ser64pro (accessed [today's date]).

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