Is ASPDH p.Leu229Pro (c.686T>C) pathogenic?

ASPDH p.Leu229Pro (c.686T>C) is classified Uncertain significance in ASPDH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely pathogenic (0.8659); Ultra-rare (popmax 0.01%, amr).

How common is ASPDH p.Leu229Pro (c.686T>C) in the general population?

ASPDH p.Leu229Pro (c.686T>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ASPDH p.Leu229Pro (c.686T>C)?

AlphaMissense predicts likely pathogenic (score 0.8659) — an in-silico prediction, not a clinical call.

ASPDH p.Leu229Pro

c.686T>C · rs375826388 · VCV2405613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8659	likely pathogenic · top 9% in ASPDH
REVEL	0.379	indeterminate
SaProt	LLR -14.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.84, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,090 bp · p 0.32 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,938 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00415% 67/1,613,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,990
Finnishnot grpmax-eligible	0.00945%	10,579
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.00441%	22,690

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: ASPDH
Protein: p.Leu229Pro
Coding: c.686T>C
MANE Select: NM_001114598
dbSNP: rs375826388
Type: single nucleotide variant
Location: chr19:50512258 (GRCh38)
Gene constraint: LOEUF 1.216 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.88

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

Similar variants

ASPDH p.Ala120Thr Uncertain significance ★ ⚠ same type
ASPDH p.Ala127Thr Uncertain significance ★ ⚠ same type
ASPDH p.Ala139Glu Uncertain significance ★ ⚠ same type
ASPDH p.Ala187Val Uncertain significance ★ ⚠ same type
ASPDH p.Ala195Glu Uncertain significance ★ ⚠ same type
ASPDH p.Ala241Thr Uncertain significance ★ ⚠ same type
ASPDH p.Ala85Glu Uncertain significance ★ ⚠ same type
ASPDH p.Arg158Gln 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/aspdh-p-leu229pro (accessed [today's date]).

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