Is MLPH p.Pro513Leu (c.1538C>T) pathogenic?

MLPH p.Pro513Leu (c.1538C>T) is classified Uncertain significance in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2846); Ultra-rare (popmax 0.0123%, afr); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Pro513Leu (c.1538C>T)?

MLPH p.Pro513Leu (c.1538C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Pro513Leu (c.1538C>T) in the general population?

MLPH p.Pro513Leu (c.1538C>T) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

What do computational predictors say about MLPH p.Pro513Leu (c.1538C>T)?

AlphaMissense predicts likely benign (score 0.2846) — an in-silico prediction, not a clinical call.

MLPH p.Pro513Leu

c.1538C>T · rs369604551 · VCV435879

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2846	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -6.62	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 4.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	31.0	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 0.0123% African / African-American · 9/72,912 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00479%

Overall 0.00555% 87/1,566,548 alleles · ultra-rare exomes 72/1,418,126 · genomes 15/148,422 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,101
Remaining individualsnot grpmax-eligible	0.00823%	12,149
Admixed American	0.00567%	17,631
European (non-Finnish)	0.00562%	17,802
East Asian	0.00467%	21,397
Finnishnot grpmax-eligible	0.00338%	29,612
South Asian	0.00117%	85,764

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.Pro513Leu
Coding: c.1538C>T
MANE Select: NM_024101
dbSNP: rs369604551
Type: single nucleotide variant
Location: chr2:237542658 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 513: 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.Pro513= Conflicting classifications of pathogenicity ★ 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-pro513leu (accessed [today's date]).

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