Is MLPH p.Pro451Ser (c.1351C>T) pathogenic?

MLPH p.Pro451Ser (c.1351C>T) is classified Benign in MLPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0844); Common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MLPH p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

MLPH p.Pro451Ser

Q: How common is MLPH p.Pro451Ser (c.1351C>T) in the general population?

MLPH p.Pro451Ser (c.1351C>T) is common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1351C>T · rs58256353 · VCV1528887

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.72	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 0.49	GERP -2.9
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	6.687	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 19.8% African / African-American · 14,813/74,976 alleles

Filtering AF 19.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.4%

Overall 1.11% 17,925/1,613,310 alleles · common exomes 9,247/1,461,076 · genomes 8,678/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	19.8%	5
Middle Eastern	2.02%	50
Admixed American	1.57%	64
Remaining individualsnot grpmax-eligible	1.56%	64
Ashkenazi Jewishnot grpmax-eligible	0.253%	395
South Asian	0.13%	772
European (non-Finnish)	0.0725%	1,378
Finnishnot grpmax-eligible	0.0394%	2,536

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.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_024101
dbSNP: rs58256353
Type: single nucleotide variant
Location: chr2:237540862 (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

Similar variants

MLPH p.Pro451= Likely benign ★ same residue
MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same type
MLPH p.Arg35Trp Pathogenic/Likely pathogenic ★★ same type
MLPH p.Ala236Thr Uncertain significance ★★ ⚠ same type
MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same type
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same type
MLPH p.Arg507Trp Uncertain significance ★★ ⚠ same type
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ 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/mlph-p-pro451ser (accessed [today's date]).

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