Is DLAT p.Ala253Ser (c.757G>T) pathogenic?

DLAT p.Ala253Ser (c.757G>T) is classified Uncertain significance in DLAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-24). AlphaMissense: likely pathogenic (0.6554); Very rare (popmax 0.00424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DLAT p.Ala253Ser (c.757G>T)?

DLAT p.Ala253Ser (c.757G>T) is associated with Inborn genetic diseases (ClinVar).

How common is DLAT p.Ala253Ser (c.757G>T) in the general population?

DLAT p.Ala253Ser (c.757G>T) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about DLAT p.Ala253Ser (c.757G>T)?

AlphaMissense predicts likely pathogenic (score 0.6554) — an in-silico prediction, not a clinical call.

DLAT p.Ala253Ser

c.757G>T · rs746422062 · VCV2663016

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6554	likely pathogenic
REVEL	0.419	indeterminate
SaProt	LLR -10.89	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.014 · regional, not allelic
Overall
CADD	27.6	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 0.00424% European (non-Finnish) · 50/1,179,894 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00335% 54/1,613,752 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,598
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00267%	37,453

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: DLAT
Protein: p.Ala253Ser
Coding: c.757G>T
MANE Select: NM_001931
dbSNP: rs746422062
Type: single nucleotide variant
Location: chr11:112033500 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 253: the lipoyl-binding 2 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DLAT p.Ala253= Likely benign ★ same residue
DLAT p.Val157Gly Likely pathogenic ★★ same condition
DLAT p.Arg429Ser Uncertain significance ★★ ⚠ same condition
DLAT p.Arg430Gln Uncertain significance ★★ ⚠ same condition
DLAT p.Arg56Pro Uncertain significance ★★ ⚠ same condition
DLAT p.Arg70Trp Uncertain significance ★★ ⚠ same condition
DLAT p.Asp390Asn Uncertain significance ★★ ⚠ same condition
DLAT p.Glu469Gly 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/dlat-p-ala253ser (accessed [today's date]).

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