Is ALDH7A1 p.Ala26Val (c.77C>T) pathogenic?

ALDH7A1 p.Ala26Val (c.77C>T) is classified Uncertain significance in ALDH7A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely benign (0.1133); Very rare (popmax 0.00135%, afr); Associated with pyridoxine-dependent epilepsy.

What condition is associated with ALDH7A1 p.Ala26Val (c.77C>T)?

ALDH7A1 p.Ala26Val (c.77C>T) is associated with pyridoxine-dependent epilepsy (ClinVar).

How common is ALDH7A1 p.Ala26Val (c.77C>T) in the general population?

ALDH7A1 p.Ala26Val (c.77C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about ALDH7A1 p.Ala26Val (c.77C>T)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

ALDH7A1 p.Ala26Val

Q: How is Pyridoxine-dependent-developmental and epileptic encephalopathy inherited?

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

c.77C>T · rs1751701268 · VCV1486951

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pyridoxine-dependent epilepsy

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.98, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 50 kb · p 0.14 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00135% African / African-American · 1/73,866 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000443% 7/1,579,380 alleles · very rare exomes 6/1,427,148 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00162%	61,624
African / African-Americangrpmax	0.00135%	73,866
European (non-Finnish)	0.00043%	232,405

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: ALDH7A1
Protein: p.Ala26Val
Coding: c.77C>T
MANE Select: NM_001182
dbSNP: rs1751701268
Type: single nucleotide variant
Location: chr5:126595122 (GRCh38)
Gene constraint: LOEUF 0.983 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.09 · 20 PDB

Full ALDH7A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pyridoxine-dependent epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pyridoxine-dependent-developmental and epileptic encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ALDH7A1 p.Ala26= Likely benign ★ same residue
ALDH7A1 p.Ala26fs Likely pathogenic ★★ same residue
ALDH7A1 c.1093+1G>A Pathogenic ★★ same condition
ALDH7A1 c.1200+1G>T Pathogenic/Likely pathogenic ★★ same condition
ALDH7A1 c.1318-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALDH7A1 c.1489+2T>C Pathogenic ★★ same condition
ALDH7A1 c.1489+5G>A Pathogenic/Likely pathogenic ★★ same condition
ALDH7A1 c.1565+1G>T Pathogenic/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/aldh7a1-p-ala26val (accessed [today's date]).

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