Is MPDZ p.Val581Phe (c.1741G>T) pathogenic?

MPDZ p.Val581Phe (c.1741G>T) is classified Uncertain significance in MPDZ (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.7528); Ultra-rare (popmax 0.0165%, mid).

How common is MPDZ p.Val581Phe (c.1741G>T) in the general population?

MPDZ p.Val581Phe (c.1741G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MPDZ p.Val581Phe (c.1741G>T)?

AlphaMissense predicts likely pathogenic (score 0.7528) — an in-silico prediction, not a clinical call.

MPDZ p.Val581Phe

c.1741G>T · rs199726781 · VCV1434200

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7528 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7528	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -13.17	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 6	GERP 2.2, phastCons 1
Overall
CADD	24.8	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

Grpmax group 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.00632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00585%

Overall 0.0117% 188/1,612,076 alleles · ultra-rare exomes 172/1,460,090 · genomes 16/151,986 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.247%	405
Remaining individualsnot grpmax-eligible	0.024%	4,159
Middle Easterngrpmax	0.0165%	6,072
European (non-Finnish)	0.00763%	13,098
South Asian	0.0055%	18,184
Admixed American	0.00501%	19,973
African / African-American	0.00134%	74,836

Ashkenazi Jewish 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: MPDZ
Protein: p.Val581Phe
Coding: c.1741G>T
MANE Select: NM_001378778
dbSNP: rs199726781
Type: single nucleotide variant
Location: chr9:13193229 (GRCh38)
Structure: AlphaFold pLDDT 72.11 · 3 PDB
Residue 581: the pdz 3 domain

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

Similar variants

MPDZ p.Val581Leu Uncertain significance ★★ ⚠ same residue
MPDZ p.Val581Ile Uncertain significance ★ ⚠ same residue
MPDZ c.1087-1G>A Pathogenic/Likely pathogenic ★★ same type
MPDZ c.1474+2T>C Likely pathogenic ★★ same type
MPDZ c.3359+1G>A Likely pathogenic ★★ same type
MPDZ c.3360-2A>G Pathogenic/Likely pathogenic ★★ same type
MPDZ c.4003+1G>A Pathogenic/Likely pathogenic ★★ same type
MPDZ p.Arg1034Ter Pathogenic/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/mpdz-p-val581phe (accessed [today's date]).

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