Is DLAT p.Pro492Ala (c.1474C>G) pathogenic?

DLAT p.Pro492Ala (c.1474C>G) is classified Uncertain significance in DLAT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.5844); Very rare (popmax 0.000254%, nfe).

How common is DLAT p.Pro492Ala (c.1474C>G) in the general population?

DLAT p.Pro492Ala (c.1474C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DLAT p.Pro492Ala (c.1474C>G)?

AlphaMissense predicts likely pathogenic (score 0.5844) — an in-silico prediction, not a clinical call.

DLAT p.Pro492Ala

c.1474C>G · rs1374987167 · VCV1686629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5844	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -10.57	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 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.014 · regional, not allelic
Overall
CADD	24.4	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 0.000254% European (non-Finnish) · 3/1,179,962 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,366 alleles · very rare

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.Pro492Ala
Coding: c.1474C>G
MANE Select: NM_001931
dbSNP: rs1374987167
Type: single nucleotide variant
Location: chr11:112051309 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.59 · 13 PDB
Residue 492: an α-helix

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

Similar variants

DLAT p.Pro492= Likely benign ★★ same residue
DLAT c.976-1G>A Pathogenic/Likely pathogenic ★★ same type
DLAT p.Arg435Ter Pathogenic ★★ same type
DLAT p.Glu138Ter Pathogenic ★★ same type
DLAT p.Val157Gly Likely pathogenic ★★ same type
DLAT c.1130-6T>G Uncertain significance ★★ same type
DLAT p.Ala109Thr Uncertain significance ★★ ⚠ same type
DLAT p.Ala191Gly 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/dlat-p-pro492ala (accessed [today's date]).

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