Is ASPG p.Arg154His (c.461G>A) pathogenic?

ASPG p.Arg154His (c.461G>A) is classified Uncertain significance in ASPG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.2249); Ultra-rare (popmax 0.017%, mid).

How common is ASPG p.Arg154His (c.461G>A) in the general population?

ASPG p.Arg154His (c.461G>A) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about ASPG p.Arg154His (c.461G>A)?

AlphaMissense predicts likely benign (score 0.2249) — an in-silico prediction, not a clinical call.

ASPG p.Arg154His

c.461G>A · rs765497573 · VCV2240554

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2249	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -10.13	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 27 kb · p 0.058 · regional, not allelic
Overall
CADD	27.2	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 0.017% Middle Eastern · 1/5,870 alleles

Filtering AF 0.00466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00343%

Overall 0.00186% 29/1,561,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,870
South Asian	0.00946%	10,571
Remaining individualsnot grpmax-eligible	0.00496%	20,173
East Asian	0.00479%	20,856
African / African-American	0.00136%	73,602
European (non-Finnish)	0.00121%	82,386

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: ASPG
Protein: p.Arg154His
Coding: c.461G>A
MANE Select: NM_001080464
dbSNP: rs765497573
Type: single nucleotide variant
Location: chr14:104097585 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 2 PDB
Residue 154: the asparaginase/glutaminase domain; the 'asparaginase' region

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

Similar variants

ASPG p.Arg154Gly Uncertain significance ★ ⚠ same residue
ASPG p.Asp223= Benign ★★ same type
ASPG c.1620+1G>A Uncertain significance ★ same type
ASPG p.Ala315Gly Uncertain significance ★ ⚠ same type
ASPG p.Ala315Val Uncertain significance ★ ⚠ same type
ASPG p.Ala332Val Uncertain significance ★ ⚠ same type
ASPG p.Ala442Thr Uncertain significance ★ ⚠ same type
ASPG p.Ala4Thr 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/aspg-p-arg154his (accessed [today's date]).

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