Is MADD p.Ile316Val (c.946A>G) pathogenic?

MADD p.Ile316Val (c.946A>G) is classified Uncertain significance in MADD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0468%, amr); Associated with Inborn genetic diseases.

What condition is associated with MADD p.Ile316Val (c.946A>G)?

MADD p.Ile316Val (c.946A>G) is associated with Inborn genetic diseases (ClinVar).

How common is MADD p.Ile316Val (c.946A>G) in the general population?

MADD p.Ile316Val (c.946A>G) is ultra-rare (popmax 0.0468%, amr) (gnomAD).

What do computational predictors say about MADD p.Ile316Val (c.946A>G)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

MADD p.Ile316Val

c.946A>G · rs764304296 · VCV3122009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -5.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Overall
CADD	22.6	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

Grpmax group 0.0468% Admixed American · 28/59,832 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0287%

Overall 0.00453% 73/1,610,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0468%	2,137
European (non-Finnish)	0.00357%	28,032
Remaining individualsnot grpmax-eligible	0.00321%	31,137
African / African-American	0.00134%	74,828

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: MADD
Protein: p.Ile316Val
Coding: c.946A>G
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs764304296
Type: single nucleotide variant
Location: chr11:47276185 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 316: the 'domain ii' region; a β-strand

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

ETFA p.Val316Leu Uncertain significance ★ ⚠ same residue
ETFA p.Val316Phe Uncertain significance ★ ⚠ same residue
ETFA p.Arg169Cys Uncertain significance ★★ ⚠ same condition
ETFA p.Arg249His Uncertain significance ★★ ⚠ same condition
ETFA p.Asp174Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gln9Arg Uncertain significance ★★ ⚠ same condition
ETFA p.Glu186Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gly181Ser 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-ile316val (accessed [today's date]).

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