Is ALDH4A1 p.Pro36= (c.108C>T) pathogenic?

ALDH4A1 p.Pro36= (c.108C>T) is classified Likely benign in ALDH4A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Very rare (popmax 0.00668%, amr); Associated with hyperprolinemia type 2.

What condition is associated with ALDH4A1 p.Pro36= (c.108C>T)?

ALDH4A1 p.Pro36= (c.108C>T) is associated with hyperprolinemia type 2 (ClinVar).

How common is ALDH4A1 p.Pro36= (c.108C>T) in the general population?

ALDH4A1 p.Pro36= (c.108C>T) is very rare (popmax 0.00668%, amr) (gnomAD).

How is Hyperprolinemia type 2 inherited?

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

ALDH4A1 p.Pro36=

c.108C>T · rs768297819 · VCV732818

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Conditions

hyperprolinemia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -2.7
Overall
CADD	9.116	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% Admixed American · 4/59,916 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00236% 38/1,613,050 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,979
Remaining individualsnot grpmax-eligible	0.0032%	31,223
European (non-Finnish)	0.00246%	40,682
East Asian	0.00223%	44,880
South Asian	0.0022%	45,420

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.Pro36=
Coding: c.108C>T
MANE Select: NM_003748
dbSNP: rs768297819
Type: single nucleotide variant
Location: chr1:18890060 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.22 · 6 PDB
Residue 36: an α-helix

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

Similar variants

ALDH4A1 c.866+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALDH4A1 p.Arg47Ter Pathogenic/Likely pathogenic ★★ same condition
ALDH4A1 c.*272C>T Uncertain significance ★★ same condition
ALDH4A1 c.*646G>A Uncertain significance ★★ same condition
ALDH4A1 p.Ala162Thr Uncertain significance ★★ ⚠ same condition
ALDH4A1 p.Ala163Thr Uncertain significance ★★ ⚠ same condition
ALDH4A1 p.Ala220Pro Uncertain significance ★★ ⚠ same condition
ALDH4A1 p.Ala238Thr 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/aldh4a1-p-pro36 (accessed [today's date]).

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