Is DLST p.Arg437Cys (c.1309C>T) pathogenic?

DLST p.Arg437Cys (c.1309C>T) is classified Uncertain significance in DLST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). AlphaMissense: ambiguous (0.3607); Ultra-rare (popmax 0.0183%, amr).

How common is DLST p.Arg437Cys (c.1309C>T) in the general population?

DLST p.Arg437Cys (c.1309C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about DLST p.Arg437Cys (c.1309C>T)?

AlphaMissense predicts ambiguous (score 0.3607) — an in-silico prediction, not a clinical call.

DLST p.Arg437Cys

c.1309C>T · rs372583375 · VCV2217142

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Computational evidence

Protein change
AlphaMissense	0.3607	ambiguous
REVEL	0.429	indeterminate
SaProt	LLR -14.03	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,926 bp · p 4e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,986 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00502% 81/1,613,420 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
East Asian	0.00891%	11,218
European (non-Finnish)	0.00543%	18,432
Remaining individualsnot grpmax-eligible	0.0032%	31,228

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: DLST
Protein: p.Arg437Cys
Coding: c.1309C>T
MANE Select: NM_001933
dbSNP: rs372583375
Type: single nucleotide variant
Location: chr14:74902277 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.40 · 2 PDB
Residue 437: an α-helix

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

Similar variants

DLST p.Ala264Val Uncertain significance ★★ ⚠ same type
DLST p.Arg4Gln Uncertain significance ★★ ⚠ same type
DLST p.Arg6Ser Uncertain significance ★★ ⚠ same type
DLST p.Asn44Ser Uncertain significance ★★ ⚠ same type
DLST p.Asn51Asp Uncertain significance ★★ ⚠ same type
DLST p.Asp304Gly Uncertain significance ★★ ⚠ same type
DLST p.Gly216Val Uncertain significance ★★ ⚠ same type
DLST p.Ile106Val 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/dlst-p-arg437cys (accessed [today's date]).

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