Is MADD p.Ser257Phe (c.770C>T) pathogenic?

MADD p.Ser257Phe (c.770C>T) is classified Pathogenic in MADD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely pathogenic (0.8586); Absent from gnomAD v4.1; Associated with deeah syndrome.

What condition is associated with MADD p.Ser257Phe (c.770C>T)?

MADD p.Ser257Phe (c.770C>T) is associated with deeah syndrome (ClinVar).

How common is MADD p.Ser257Phe (c.770C>T) in the general population?

MADD p.Ser257Phe (c.770C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MADD p.Ser257Phe (c.770C>T)?

AlphaMissense predicts likely pathogenic (score 0.8586) — an in-silico prediction, not a clinical call.

MADD p.Ser257Phe

Q: How is MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.770C>T · rs2049504624 · VCV978086

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8586 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

deeah syndrome

Computational evidence

Protein change
AlphaMissense	0.8586	likely pathogenic ✓ concordant with ClinVar
REVEL	0.464	indeterminate
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Overall
CADD	25.6	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.Ser257Phe
Coding: c.770C>T
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs2049504624
Type: single nucleotide variant
Location: chr11:47276009 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 257: the 'domain ii' region

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

Disease context

deeah syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

ETFA p.Val257= Likely benign ★ same residue
ETFA p.Val257Ile Uncertain significance ⚠ same residue
MADD c.2816+1G>A 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-ser257phe (accessed [today's date]).

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