Is ASPA p.Arg71His (c.212G>A) pathogenic?

ASPA p.Arg71His (c.212G>A) is classified Pathogenic/Likely pathogenic in ASPA (ClinVar, Multiple submitters, 14 submitters; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.7629); Very rare (popmax 0.00667%, amr); Associated with ASPA-related disorder.

What condition is associated with ASPA p.Arg71His (c.212G>A)?

ASPA p.Arg71His (c.212G>A) is associated with ASPA-related disorder, Canavan disease, mild Canavan disease (ClinVar).

How common is ASPA p.Arg71His (c.212G>A) in the general population?

ASPA p.Arg71His (c.212G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ASPA p.Arg71His (c.212G>A)?

AlphaMissense predicts likely pathogenic (score 0.7629) — an in-silico prediction, not a clinical call.

ASPA p.Arg71His

c.212G>A · rs104894553 · VCV2616

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.7629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ASPA-related disorder

Computational evidence

Protein change
AlphaMissense	0.7629	likely pathogenic ✓ concordant with ClinVar
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 23 kb · p 0.0073 · regional, not allelic
Overall
CADD	33.0	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 0.00667% Admixed American · 4/60,002 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.0112% 181/1,613,924 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.194%	516
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00415%	24,082
South Asian	0.0011%	91,090

Finnish 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: ASPA
Protein: p.Arg71His
Coding: c.212G>A
MANE Select: NM_000049
dbSNP: rs104894553
Type: single nucleotide variant
Location: chr17:3476371 (GRCh38)
Gene constraint: LOEUF 1.098 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.14 · 8 PDB
Residue 71: a binding site; an α-helix

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

Disease context

ASPA-related disorder

Also linked: Canavan disease mild Canavan disease

Similar variants

ASPA p.Arg71Leu Likely pathogenic ★ same residue
ASPA p.Arg71Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ASPA p.Arg71= Likely benign ★ same residue
ASPA c.236+2T>C Likely pathogenic ★★ same condition
ASPA c.237-1G>T Likely pathogenic ★★ same condition
ASPA c.237-2A>T Pathogenic/Likely pathogenic ★★ same condition
ASPA c.527-1G>A Likely pathogenic ★★ same condition
ASPA c.527-2A>C Likely pathogenic ★★ 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/aspa-p-arg71his (accessed [today's date]).

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