Is ALAS2 p.Arg16Trp (c.46C>T) pathogenic?

ALAS2 p.Arg16Trp (c.46C>T) is classified Likely benign in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1375); Ultra-rare (popmax 0.0334%, sas).

How common is ALAS2 p.Arg16Trp (c.46C>T) in the general population?

ALAS2 p.Arg16Trp (c.46C>T) is ultra-rare (popmax 0.0334%, sas) (gnomAD).

What do computational predictors say about ALAS2 p.Arg16Trp (c.46C>T)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

ALAS2 p.Arg16Trp

c.46C>T · rs780949974 · VCV1970123

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.65, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,159 bp · p 0.19 · regional, not allelic
Overall
CADD	20.2	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 0.0334% South Asian · 19/56,907 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00246% 27/1,097,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0334%	2,995
Remaining individualsnot grpmax-eligible	0.0084%	11,907
East Asian	0.00296%	33,800
European (non-Finnish)	0.000335%	298,426

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.Arg16Trp
Coding: c.46C>T
MANE Select: NM_000032
dbSNP: rs780949974
Type: single nucleotide variant
Location: chrX:55025955 (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.Arg16Gln Benign/Likely benign ★★ same residue
ALAS2 p.Arg16= Likely benign ★ 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

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-arg16trp (accessed [today's date]).

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