Is MADD p.Ser1234Phe (c.3701C>T) pathogenic?

MADD p.Ser1234Phe (c.3701C>T) is classified Uncertain significance in MADD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.2004); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MADD p.Ser1234Phe (c.3701C>T)?

MADD p.Ser1234Phe (c.3701C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MADD p.Ser1234Phe (c.3701C>T) in the general population?

MADD p.Ser1234Phe (c.3701C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MADD p.Ser1234Phe (c.3701C>T)?

AlphaMissense predicts likely benign (score 0.2004) — an in-silico prediction, not a clinical call.

MADD p.Ser1234Phe

c.3701C>T · rs780886642 · VCV2269489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2004 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2004	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Ser1234Phe
Coding: c.3701C>T
MANE Select: NM_001376571
dbSNP: rs780886642
Type: single nucleotide variant
Location: chr11:47295997 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.59
Residue 1234: the 'disordered' region; a UniProt-annotated variant site (in deeah; uncertain significance); a UniProt-annotated variant site (in deeah and neddish; uncertain significance); a UniProt-annotated variant site (in neddish; impaired tnfa-induced activation of the map kinases erk1/2; enhanced susceptibility to tnfa-induced apoptosis; decreased egf internalization)

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-ser1234phe (accessed [today's date]).

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