Is ALDH4A1 p.Pro459= (c.1377G>C) pathogenic?

ALDH4A1 p.Pro459= (c.1377G>C) is classified Conflicting classifications of pathogenicity in ALDH4A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0993%, nfe); Associated with hyperprolinemia type 2.

What condition is associated with ALDH4A1 p.Pro459= (c.1377G>C)?

ALDH4A1 p.Pro459= (c.1377G>C) is associated with hyperprolinemia type 2 (ClinVar).

How common is ALDH4A1 p.Pro459= (c.1377G>C) in the general population?

ALDH4A1 p.Pro459= (c.1377G>C) is ultra-rare (popmax 0.0993%, nfe) (gnomAD).

How is Hyperprolinemia type 2 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ALDH4A1 p.Pro459=

c.1377G>C · rs146222625 · VCV294370

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0993%, nfe)

Conditions

hyperprolinemia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -20	GERP -3.7
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0993% European (non-Finnish) · 1,172/1,180,012 alleles

Filtering AF 0.0945% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.0766% 1,236/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0993%	1,007
Remaining individualsnot grpmax-eligible	0.064%	1,562
Admixed American	0.0167%	6,001
African / African-American	0.0134%	7,490
Finnishnot grpmax-eligible	0.00468%	21,347
South Asian	0.0011%	91,086

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: ALDH4A1
Protein: p.Pro459=
Coding: c.1377G>C
dbSNP: rs146222625
Type: single nucleotide variant
Location: chr1:18875465 (GRCh38)

Full ALDH4A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperprolinemia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperprolinemia type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

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/aldh4a1-p-pro459 (accessed [today's date]).

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