Is MLPH p.His347Arg (c.1040A>G) pathogenic?

MLPH p.His347Arg (c.1040A>G) is classified Benign in MLPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0523); Common (popmax 57.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MLPH p.His347Arg (c.1040A>G)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

MLPH p.His347Arg

Q: How common is MLPH p.His347Arg (c.1040A>G) in the general population?

MLPH p.His347Arg (c.1040A>G) is common (popmax 57.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1040A>G · rs2292884 · VCV1229855

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -4.22	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 -1.8	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	0.044	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 57.3% African / African-American · 42,836/74,810 alleles

Filtering AF 56.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.6%

Overall 27.2% 439,093/1,611,710 alleles · common exomes 387,415/1,459,736 · genomes 51,678/151,974 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	57.3%	2
South Asian	34%	3
Admixed American	30%	3
Middle Eastern	29.7%	3
Remaining individualsnot grpmax-eligible	28.7%	3
Ashkenazi Jewishnot grpmax-eligible	26.4%	4
East Asian	26.2%	4
European (non-Finnish)	25%	4
Amishnot grpmax-eligible	20.2%	5
Finnishnot grpmax-eligible	20.1%	5

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.His347Arg
Coding: c.1040A>G
MANE Select: NM_024101
dbSNP: rs2292884
Type: single nucleotide variant
Location: chr2:237534583 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 347: a UniProt-annotated variant site (in)

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-his347arg (accessed [today's date]).

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