Is MLPH p.Gln72Arg (c.215A>G) pathogenic?

MLPH p.Gln72Arg (c.215A>G) is classified Benign in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0485); Common (popmax 5.36%, sas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MLPH p.Gln72Arg (c.215A>G)?

AlphaMissense predicts likely benign (score 0.0485) — an in-silico prediction, not a clinical call.

MLPH p.Gln72Arg

Q: How common is MLPH p.Gln72Arg (c.215A>G) in the general population?

MLPH p.Gln72Arg (c.215A>G) is common (popmax 5.36%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.215A>G · rs80292002 · VCV1599849

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0485 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.36%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0485	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -3.13	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 1.7	GERP -1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	7.903	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 5.36% South Asian · 4,879/91,084 alleles

Filtering AF 5.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.18%

Overall 0.697% 11,255/1,613,788 alleles · common exomes 9,932/1,461,444 · genomes 1,323/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	5.36%	19
East Asian	3.13%	32
Admixed American	2.6%	39
Finnishnot grpmax-eligible	2.38%	42
Remaining individualsnot grpmax-eligible	0.91%	110
African / African-American	0.862%	116
Middle Eastern	0.314%	319
European (non-Finnish)	0.0561%	1,783

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.Gln72Arg
Coding: c.215A>G
MANE Select: NM_024101
dbSNP: rs80292002
Type: single nucleotide variant
Location: chr2:237510678 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 72: the rabbd domain

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-gln72arg (accessed [today's date]).

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