Is MLPH p.Ser503Leu (c.1508C>T) pathogenic?

MLPH p.Ser503Leu (c.1508C>T) is classified Benign/Likely benign in MLPH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-29). AlphaMissense: likely benign (0.0966); Low-frequency (popmax 2.31%, afr).

How common is MLPH p.Ser503Leu (c.1508C>T) in the general population?

MLPH p.Ser503Leu (c.1508C>T) is low-frequency (popmax 2.31%, afr) (gnomAD).

What do computational predictors say about MLPH p.Ser503Leu (c.1508C>T)?

AlphaMissense predicts likely benign (score 0.0966) — an in-silico prediction, not a clinical call.

MLPH p.Ser503Leu

c.1508C>T · rs146485666 · VCV775835

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0966 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.31%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0966	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.09	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 3.2	GERP 1.9, phastCons 0.74
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	21.7	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 2.31% African / African-American · 1,718/74,482 alleles

Filtering AF 2.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.18%

Overall 0.127% 2,023/1,596,926 alleles · low-frequency exomes 1,072/1,445,504 · genomes 951/151,422 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.31%	43
Remaining individualsnot grpmax-eligible	0.15%	665
Admixed American	0.141%	712
South Asian	0.103%	970
Middle Eastern	0.0507%	1,971
East Asian	0.00903%	11,071
European (non-Finnish)	0.00281%	35,544

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.Ser503Leu
Coding: c.1508C>T
MANE Select: NM_024101
dbSNP: rs146485666
Type: single nucleotide variant
Location: chr2:237542628 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 503: the 'disordered' region

Full MLPH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MLPH p.Ser503Ter Pathogenic ★ same residue
MLPH p.Ser503= 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

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-ser503leu (accessed [today's date]).

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