Is MLPH p.Pro451= (c.1353C>T) pathogenic?

MLPH p.Pro451= (c.1353C>T) is classified Likely benign in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Pro451= (c.1353C>T)?

MLPH p.Pro451= (c.1353C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Pro451= (c.1353C>T) in the general population?

MLPH p.Pro451= (c.1353C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

MLPH p.Pro451=

c.1353C>T · VCV4108804

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.02	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -3.8
Overall
CADD	1.214	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,976 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000806% 13/1,613,250 alleles · ultra-rare exomes 10/1,461,048 · genomes 3/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,996
Remaining individualsnot grpmax-eligible	0.0032%	31,231
African / African-American	0.00267%	37,457
European (non-Finnish)	0.000254%	393,323

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.Pro451=
Coding: c.1353C>T
MANE Select: NM_024101
Type: single nucleotide variant
Location: chr2:237540864 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 451: a UniProt-annotated variant site (in); 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.Pro451Ser Benign ★★ 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-pro451 (accessed [today's date]).

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