Is ASPH p.Arg425His (c.1274G>A) pathogenic?

ASPH p.Arg425His (c.1274G>A) is classified Uncertain significance in ASPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: ambiguous (0.3618); Ultra-rare (popmax 0.0912%, sas); Associated with Inborn genetic diseases.

What condition is associated with ASPH p.Arg425His (c.1274G>A)?

ASPH p.Arg425His (c.1274G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ASPH p.Arg425His (c.1274G>A) in the general population?

ASPH p.Arg425His (c.1274G>A) is ultra-rare (popmax 0.0912%, sas) (gnomAD).

What do computational predictors say about ASPH p.Arg425His (c.1274G>A)?

AlphaMissense predicts ambiguous (score 0.3618) — an in-silico prediction, not a clinical call.

ASPH p.Arg425His

c.1274G>A · VCV3953254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0912%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3618	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 211 kb · p 0.99 · regional, not allelic
Overall
CADD	25.1	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 0.0912% South Asian · 83/91,042 alleles

Filtering AF 0.0753% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0694%

Overall 0.00657% 106/1,613,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0912%	1,097
Middle Eastern	0.0165%	6,062
Admixed American	0.005%	19,991
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00313%	31,994
Remaining individualsnot grpmax-eligible	0.0016%	62,498
African / African-American	0.00133%	75,022
European (non-Finnish)	0.00119%	84,279

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: ASPH
Protein: p.Arg425His
Coding: c.1274G>A
MANE Select: NM_004318
Type: single nucleotide variant
Location: chr8:61567194 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 43 PDB
Residue 425: an α-helix

Full ASPH 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

ASPH p.Arg425Cys Uncertain significance ★★ ⚠ same residue
ASPH p.Arg753His Uncertain significance ★★ ⚠ same condition
ASPH p.Glu506Val Uncertain significance ★★ same condition
ASPH p.Leu433Arg Uncertain significance ★★ ⚠ same condition
ASPH p.Ser299Asn Uncertain significance ★★ ⚠ same condition
ASPH p.Val214Met Uncertain significance ★★ ⚠ same condition
ASPH p.Val462Met Uncertain significance ★★ ⚠ same condition
ASPH p.Val83Ala 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/asph-p-arg425his (accessed [today's date]).

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