Is DES p.Pro148Leu (c.443C>T) pathogenic?

DES p.Pro148Leu (c.443C>T) is classified Uncertain significance in DES (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.5647); Very rare (popmax 0.00156%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DES p.Pro148Leu (c.443C>T)?

DES p.Pro148Leu (c.443C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 1 (ClinVar).

How common is DES p.Pro148Leu (c.443C>T) in the general population?

DES p.Pro148Leu (c.443C>T) is very rare (popmax 0.00156%, nfe) (gnomAD).

What do computational predictors say about DES p.Pro148Leu (c.443C>T)?

AlphaMissense predicts likely pathogenic (score 0.5647) — an in-silico prediction, not a clinical call.

DES p.Pro148Leu

c.443C>T · VCV3839552

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00156%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5647	likely pathogenic
REVEL	0.682	pathogenic-leaning
SaProt	LLR -12.69	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 -2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,524 bp · p 0.05 · regional, not allelic
Overall
CADD	31.0	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 0.00156% European (non-Finnish) · 18/1,154,134 alleles

Filtering AF 0.000975% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000804%

Overall 0.00135% 19/1,411,550 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00156%	64,119
African / African-American	0.00135%	73,892

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: DES
Protein: p.Pro148Leu
Coding: c.443C>T
MANE Select: NM_001927
Type: single nucleotide variant
Location: chr2:219418905 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73
Residue 148: the if rod domain; the 'linker 1' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 1

Similar variants

DES p.Pro148= Likely benign ★★ same residue
DES p.Pro148Gln Uncertain significance ★ ⚠ same residue
DES c.1289-2A>G Pathogenic/Likely pathogenic ★★ same condition
DES c.579-2A>C Likely pathogenic ★★ same condition
DES c.735+1G>A Pathogenic/Likely pathogenic ★★ same condition
DES c.735+1G>C Pathogenic/Likely pathogenic ★★ same condition
DES c.735+3A>G Pathogenic ★★ same condition
DES p.Ala120Pro 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/des-p-pro148leu (accessed [today's date]).

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