Is MLPH p.His322= (c.966C>T) pathogenic?

MLPH p.His322= (c.966C>T) is classified Benign/Likely benign in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-15). Rare (popmax 0.931%, eas).

How common is MLPH p.His322= (c.966C>T) in the general population?

MLPH p.His322= (c.966C>T) is rare (popmax 0.931%, eas) (gnomAD).

MLPH p.His322=

c.966C>T · rs75980625 · VCV2652054

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.931%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.026	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.22	GERP -1.2
Overall
CADD	4.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.931% East Asian · 418/44,886 alleles

Filtering AF 0.858% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.829%

Overall 0.176% 2,834/1,614,190 alleles · rare exomes 2,359/1,461,888 · genomes 475/152,302 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.12%	32
East Asiangrpmax	0.931%	107
Remaining individualsnot grpmax-eligible	0.149%	672
Middle Eastern	0.115%	866
South Asian	0.0538%	1,859
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0218%	4,592
African / African-American	0.00266%	37,526

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His322=
Coding: c.966C>T
MANE Select: NM_024101
dbSNP: rs75980625
Type: single nucleotide variant
Location: chr2:237527462 (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

Similar variants

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
MLPH p.Asp194Asn 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-his322 (accessed [today's date]).

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