Is MADD p.Ala165Val (c.494C>T) pathogenic?

MADD p.Ala165Val (c.494C>T) is classified Uncertain significance in MADD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-13). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.049%, eas).

How common is MADD p.Ala165Val (c.494C>T) in the general population?

MADD p.Ala165Val (c.494C>T) is ultra-rare (popmax 0.049%, eas) (gnomAD).

What do computational predictors say about MADD p.Ala165Val (c.494C>T)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

MADD p.Ala165Val

c.494C>T · rs138776960 · VCV1700868

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.18	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 -1.1	GERP -5
Overall
CADD	15.62	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 0.049% East Asian · 22/44,880 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0209% 338/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
East Asiangrpmax	0.049%	2,040
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
Admixed American	0.035%	2,859
European (non-Finnish)	0.0231%	4,338
Remaining individualsnot grpmax-eligible	0.008%	12,494
African / African-American	0.00267%	37,523
South Asian	0.0011%	91,090

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala165Val
Coding: c.494C>T
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs138776960
Type: single nucleotide variant
Location: chr11:47274994 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 165: the 'domain i' region; a β-strand

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

Similar variants

ETFA p.Val165Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MADD p.Ala165Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ETFA p.Val165= Likely benign ★ same residue
ETFA c.186+1G>A Likely pathogenic ★★ same type
ETFA c.39+1G>A Likely pathogenic ★★ same type
ETFA c.451+1G>A Likely pathogenic ★★ same type
ETFA c.452-2A>G Likely pathogenic ★★ same type
ETFA c.664+1G>A Likely pathogenic ★★ same type

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-ala165val (accessed [today's date]).

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