Is MADD p.Phe339Ser (c.1016T>C) pathogenic?

MADD p.Phe339Ser (c.1016T>C) is classified Uncertain significance in MADD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-12). AlphaMissense: likely pathogenic (0.9935); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MADD p.Phe339Ser (c.1016T>C)?

MADD p.Phe339Ser (c.1016T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MADD p.Phe339Ser (c.1016T>C) in the general population?

MADD p.Phe339Ser (c.1016T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MADD p.Phe339Ser (c.1016T>C)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

MADD p.Phe339Ser

c.1016T>C · rs2050344818 · VCV3121979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic · top 4% in MADD
REVEL	0.631	indeterminate
SaProt	LLR -13.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Overall
CADD	24.9	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

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.Phe339Ser
Coding: c.1016T>C
MANE Select: NM_001376571
dbSNP: rs2050344818
Type: single nucleotide variant
Location: chr11:47276784 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.59
Residue 339: the cdenn domain; a UniProt-annotated variant site (in deeah; uncertain significance); a UniProt-annotated variant site (in deeah and neddish; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MADD p.Ala1029Val Uncertain significance ★★ ⚠ same condition
MADD p.Arg1077Gly Uncertain significance ★★ ⚠ same condition
MADD p.Arg1273His Uncertain significance ★★ ⚠ same condition
MADD p.Arg170His Uncertain significance ★★ ⚠ same condition
MADD p.Arg699His Uncertain significance ★★ ⚠ same condition
MADD p.Arg754Cys Uncertain significance ★★ ⚠ same condition
MADD p.Arg855Gln Uncertain significance ★★ ⚠ same condition
MADD p.Asp752Gly 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-phe339ser (accessed [today's date]).

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