Is MLPH p.Ala582Val (c.1745C>T) pathogenic?

MLPH p.Ala582Val (c.1745C>T) is classified Conflicting classifications of pathogenicity in MLPH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.1263); Very rare (popmax 0.0072%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Ala582Val (c.1745C>T)?

MLPH p.Ala582Val (c.1745C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Ala582Val (c.1745C>T) in the general population?

MLPH p.Ala582Val (c.1745C>T) is very rare (popmax 0.0072%, nfe) (gnomAD).

What do computational predictors say about MLPH p.Ala582Val (c.1745C>T)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

MLPH p.Ala582Val

c.1745C>T · rs112711398 · VCV1337080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.47	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 5.4	GERP 0.59, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	22.8	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

Grpmax group 0.0072% European (non-Finnish) · 85/1,179,998 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.0253% 408/1,613,854 alleles · very rare exomes 360/1,461,846 · genomes 48/152,008 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.973%	103
Remaining individualsnot grpmax-eligible	0.0464%	2,154
European (non-Finnish)grpmax	0.0072%	13,882
Admixed American	0.005%	19,997
African / African-American	0.00267%	37,417
South Asian	0.0011%	91,066

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: MLPH
Protein: p.Ala582Val
Coding: c.1745C>T
MANE Select: NM_024101
dbSNP: rs112711398
Type: single nucleotide variant
Location: chr2:237552406 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 582: the 'disordered' region

Full MLPH 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

MLPH p.Ala582Thr Uncertain significance ★ ⚠ same residue
MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same condition
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same condition
MLPH p.Arg507Trp Uncertain significance ★★ ⚠ same condition
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same condition
MLPH p.Asp194Asn Uncertain significance ★★ ⚠ same condition
MLPH p.Asp310Asn Uncertain significance ★★ ⚠ same condition
MLPH p.Gln208His 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/mlph-p-ala582val (accessed [today's date]).

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