Is MLPH p.Arg331Gln (c.992G>A) pathogenic?

MLPH p.Arg331Gln (c.992G>A) is classified Conflicting classifications of pathogenicity in MLPH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0798); Rare (popmax 0.396%, afr); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Arg331Gln (c.992G>A)?

MLPH p.Arg331Gln (c.992G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Arg331Gln (c.992G>A) in the general population?

MLPH p.Arg331Gln (c.992G>A) is rare (popmax 0.396%, afr) (gnomAD).

What do computational predictors say about MLPH p.Arg331Gln (c.992G>A)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

MLPH p.Arg331Gln

c.992G>A · rs113169138 · VCV1305772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.396%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -7.99	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 -0.92	GERP -4.2
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	6.915	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 0.396% African / African-American · 297/75,056 alleles

Filtering AF 0.359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.344%

Overall 0.0234% 377/1,614,196 alleles · rare exomes 209/1,461,890 · genomes 168/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.396%	253
Remaining individualsnot grpmax-eligible	0.0464%	2,156
Middle Eastern	0.033%	3,031
Admixed American	0.0183%	5,457
South Asian	0.00878%	11,384
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00246%	40,691

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.Arg331Gln
Coding: c.992G>A
MANE Select: NM_024101
dbSNP: rs113169138
Type: single nucleotide variant
Location: chr2:237527488 (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-arg331gln (accessed [today's date]).

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