Is ASL p.Asp449His (c.1345G>C) pathogenic?

ASL p.Asp449His (c.1345G>C) is classified Uncertain significance in ASL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.2514); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ASL p.Asp449His (c.1345G>C)?

ASL p.Asp449His (c.1345G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ASL p.Asp449His (c.1345G>C) in the general population?

ASL p.Asp449His (c.1345G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ASL p.Asp449His (c.1345G>C)?

AlphaMissense predicts likely benign (score 0.2514) — an in-silico prediction, not a clinical call.

ASL p.Asp449His

c.1345G>C · rs781031440 · VCV2291589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2514	likely benign
REVEL	0.432	indeterminate
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 3.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 17 kb · p 0.00078 · regional, not allelic
Overall
CADD	17.55	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 0.000254% European (non-Finnish) · 3/1,179,966 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,496 alleles · very rare

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: ASL
Protein: p.Asp449His
Coding: c.1345G>C
MANE Select: NM_000048
dbSNP: rs781031440
Type: single nucleotide variant
Location: chr7:66092862 (GRCh38)
Gene constraint: LOEUF 0.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.51 · 2 PDB
Residue 449: an α-helix

Full ASL 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

ASL p.Asp449Asn Uncertain significance ★★ ⚠ same residue
ASL p.Arg186Gln Pathogenic ★★ ⚠ same condition
ASL p.Ala26Thr Uncertain significance ★★ ⚠ same condition
ASL p.Ala2Asp Uncertain significance ★★ ⚠ same condition
ASL p.Arg151His Uncertain significance ★★ ⚠ same condition
ASL p.Arg32Trp Uncertain significance ★★ ⚠ same condition
ASL p.Val196Ile Uncertain significance ★★ ⚠ same condition
ASL c.348+5T>C 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/asl-p-asp449his (accessed [today's date]).

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