Is AASDH p.Arg449His (c.1346G>A) pathogenic?

AASDH p.Arg449His (c.1346G>A) is classified Uncertain significance in AASDH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). AlphaMissense: ambiguous (0.5144); Very rare (popmax 0.0055%, sas).

How common is AASDH p.Arg449His (c.1346G>A) in the general population?

AASDH p.Arg449His (c.1346G>A) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about AASDH p.Arg449His (c.1346G>A)?

AlphaMissense predicts ambiguous (score 0.5144) — an in-silico prediction, not a clinical call.

AASDH p.Arg449His

c.1346G>A · VCV3263657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Computational evidence

Protein change
AlphaMissense	0.5144	ambiguous
REVEL	0.424	indeterminate
SaProt	LLR -9.40	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 46 kb · p 0.076 · regional, not allelic
Overall
CADD	29.0	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 0.0055% South Asian · 5/90,848 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00093% 15/1,612,632 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,609
South Asiangrpmax	0.0055%	18,170
African / African-American	0.00267%	37,409
Finnishnot grpmax-eligible	0.00156%	63,926
European (non-Finnish)	0.000254%	393,096

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AASDH
Protein: p.Arg449His
Coding: c.1346G>A
MANE Select: NM_181806
Type: single nucleotide variant
Location: chr4:56354076 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.50

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

Similar variants

AASDH p.Ile61Val Benign ★★ same type
AASDH p.Ala274Val Uncertain significance ★ ⚠ same type
AASDH p.Ala643Asp Uncertain significance ★ ⚠ same type
AASDH p.Ala643Thr Uncertain significance ★ ⚠ same type
AASDH p.Ala705Gly Uncertain significance ★ ⚠ same type
AASDH p.Ala878Thr Uncertain significance ★ ⚠ same type
AASDH p.Ala880Thr Uncertain significance ★ ⚠ same type
AASDH p.Arg1019Thr 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/aasdh-p-arg449his (accessed [today's date]).

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