Is ALDH6A1 p.Gly467Glu (c.1400G>A) pathogenic?

ALDH6A1 p.Gly467Glu (c.1400G>A) is classified Uncertain significance in ALDH6A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-21). AlphaMissense: likely pathogenic (0.9955); Very rare (popmax 0.00134%, afr); Associated with methylmalonate semialdehyde dehydrogenase deficiency.

What condition is associated with ALDH6A1 p.Gly467Glu (c.1400G>A)?

ALDH6A1 p.Gly467Glu (c.1400G>A) is associated with methylmalonate semialdehyde dehydrogenase deficiency (ClinVar).

How common is ALDH6A1 p.Gly467Glu (c.1400G>A) in the general population?

ALDH6A1 p.Gly467Glu (c.1400G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ALDH6A1 p.Gly467Glu (c.1400G>A)?

AlphaMissense predicts likely pathogenic (score 0.9955) — an in-silico prediction, not a clinical call.

ALDH6A1 p.Gly467Glu

Q: How is Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency inherited?

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

c.1400G>A · rs747566637 · VCV314171

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonate semialdehyde dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.9955	likely pathogenic · top 2% in ALDH6A1
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -13.93	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 7.4	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	26.5	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 0.00134% African / African-American · 1/74,890 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,613,944 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,890
European (non-Finnish)	0.000763%	131,112

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: ALDH6A1
Protein: p.Gly467Glu
Coding: c.1400G>A
MANE Select: NM_005589
dbSNP: rs747566637
Type: single nucleotide variant
Location: chr14:74065185 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.98 · 5 PDB
Residue 467: a β-strand

Full ALDH6A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methylmalonate semialdehyde dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ALDH6A1 c.186+6C>T Uncertain significance ★★ same condition
ALDH6A1 c.*1534G>A Uncertain significance ★★ same condition
ALDH6A1 c.*1938A>G Uncertain significance ★★ same condition
ALDH6A1 p.Arg458Gln Uncertain significance ★★ ⚠ same condition
ALDH6A1 p.Asn303Ser Uncertain significance ★★ ⚠ same condition
ALDH6A1 p.Gly216Arg Uncertain significance ★★ ⚠ same condition
ALDH6A1 p.His276Arg Uncertain significance ★★ ⚠ same condition
ALDH6A1 p.Ile83Thr 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/aldh6a1-p-gly467glu (accessed [today's date]).

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