Is DLST p.Pro186Leu (c.557C>T) pathogenic?

DLST p.Pro186Leu (c.557C>T) is classified Uncertain significance in DLST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.1027); Ultra-rare (popmax 0.0117%, nfe).

How common is DLST p.Pro186Leu (c.557C>T) in the general population?

DLST p.Pro186Leu (c.557C>T) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

What do computational predictors say about DLST p.Pro186Leu (c.557C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

DLST p.Pro186Leu

c.557C>T · VCV3502463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -11.64	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.5	GERP -1.1, phastCons 0.14
Regional constraint	o/e 1.00	unconstrained · MANE · 3,281 bp · p 1 · regional, not allelic
Overall
CADD	15.91	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 0.0117% European (non-Finnish) · 138/1,180,006 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00948%

Overall 0.00936% 151/1,613,906 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0117%	8,551
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Finnishnot grpmax-eligible	0.00469%	21,343
Admixed American	0.00334%	29,966
African / African-American	0.00267%	37,455
East Asian	0.00223%	44,894
South Asian	0.0011%	91,060

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.Pro186Leu
Coding: c.557C>T
MANE Select: NM_001933
Type: single nucleotide variant
Location: chr14:74892948 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.40 · 2 PDB
Residue 186: the 'disordered' region

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

Similar variants

DLST p.Pro186Ala Uncertain significance ★★ ⚠ same residue
DLST p.Ala264Val Uncertain significance ★★ ⚠ same type
DLST p.Arg437Cys 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

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-pro186leu (accessed [today's date]).

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