Is MADD p.Leu346Pro (c.1037T>C) pathogenic?

MADD p.Leu346Pro (c.1037T>C) is classified Conflicting classifications of pathogenicity in MADD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-08-05). AlphaMissense: likely pathogenic (0.9644); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia.

How common is MADD p.Leu346Pro (c.1037T>C) in the general population?

MADD p.Leu346Pro (c.1037T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MADD p.Leu346Pro (c.1037T>C)?

AlphaMissense predicts likely pathogenic (score 0.9644) — an in-silico prediction, not a clinical call.

MADD p.Leu346Pro

Q: What condition is associated with MADD p.Leu346Pro (c.1037T>C)?

MADD p.Leu346Pro (c.1037T>C) is associated with neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, deeah syndrome (ClinVar).

c.1037T>C · rs1591767154 · VCV806672

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9644 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

Computational evidence

Protein change
AlphaMissense	0.9644	likely pathogenic
REVEL	0.769	pathogenic-leaning
SaProt	LLR -16.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MADD
Protein: p.Leu346Pro
Coding: c.1037T>C
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs1591767154
Type: single nucleotide variant
Location: chr11:47276805 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB

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

Disease context

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: deeah syndrome

Similar variants

MADD c.2816+1G>A Pathogenic ★★ same condition
MADD p.Arg1532Ter Pathogenic ★★ same condition
MADD p.Arg327Ter Pathogenic/Likely pathogenic ★★ same condition
MADD p.Ala1029Val Uncertain significance ★★ ⚠ same condition
MADD p.Arg754Cys Uncertain significance ★★ ⚠ same condition
MADD p.Cys648Phe Uncertain significance ★★ ⚠ same condition
MADD p.Ile1159Met Uncertain significance ★★ ⚠ same condition
MADD p.Pro372Leu 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/madd-p-leu346pro (accessed [today's date]).

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