Is MLPH p.Val452Ile (c.1354G>A) pathogenic?

MLPH p.Val452Ile (c.1354G>A) is classified Uncertain significance in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0516%, sas); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Val452Ile (c.1354G>A)?

MLPH p.Val452Ile (c.1354G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Val452Ile (c.1354G>A) in the general population?

MLPH p.Val452Ile (c.1354G>A) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

What do computational predictors say about MLPH p.Val452Ile (c.1354G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

MLPH p.Val452Ile

c.1354G>A · rs544688545 · VCV2220663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.4	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	0.01	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 0.0516% South Asian · 47/91,046 alleles

Filtering AF 0.0399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00521% 84/1,613,340 alleles · ultra-rare exomes 73/1,461,056 · genomes 11/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,937
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.00933%	10,718
European (non-Finnish)	0.00203%	49,164

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.Val452Ile
Coding: c.1354G>A
MANE Select: NM_024101
dbSNP: rs544688545
Type: single nucleotide variant
Location: chr2:237540865 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 452: 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.Val452Leu 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-val452ile (accessed [today's date]).

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