Is MLPH p.Pro278Leu (c.833C>T) pathogenic?

MLPH p.Pro278Leu (c.833C>T) is classified Likely benign in MLPH (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-22). AlphaMissense: likely benign (0.0545); Rare (popmax 0.528%, sas); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Pro278Leu (c.833C>T)?

MLPH p.Pro278Leu (c.833C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Pro278Leu (c.833C>T) in the general population?

MLPH p.Pro278Leu (c.833C>T) is rare (popmax 0.528%, sas) (gnomAD).

What do computational predictors say about MLPH p.Pro278Leu (c.833C>T)?

AlphaMissense predicts likely benign (score 0.0545) — an in-silico prediction, not a clinical call.

MLPH p.Pro278Leu

c.833C>T · rs139390935 · VCV2223892

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0545 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.528%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0545	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.41	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 -10	GERP -4.2
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	0.002	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 0.528% South Asian · 481/91,074 alleles

Filtering AF 0.489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.474%

Overall 0.0434% 701/1,613,816 alleles · rare exomes 666/1,461,488 · genomes 35/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.528%	189
Remaining individualsnot grpmax-eligible	0.056%	1,786
Middle Eastern	0.0498%	2,009
European (non-Finnish)	0.0149%	6,705
East Asian	0.00668%	14,963
African / African-American	0.004%	25,017

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.Pro278Leu
Coding: c.833C>T
MANE Select: NM_024101
dbSNP: rs139390935
Type: single nucleotide variant
Location: chr2:237525758 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58

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.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
MLPH p.Glu33Lys 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-pro278leu (accessed [today's date]).

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