Is MLPH p.Ile341Phe (c.1021A>T) pathogenic?

MLPH p.Ile341Phe (c.1021A>T) is classified Uncertain significance in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.1719); Ultra-rare (popmax 0.045%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Ile341Phe (c.1021A>T)?

MLPH p.Ile341Phe (c.1021A>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Ile341Phe (c.1021A>T) in the general population?

MLPH p.Ile341Phe (c.1021A>T) is ultra-rare (popmax 0.045%, nfe) (gnomAD).

What do computational predictors say about MLPH p.Ile341Phe (c.1021A>T)?

AlphaMissense predicts likely benign (score 0.1719) — an in-silico prediction, not a clinical call.

MLPH p.Ile341Phe

c.1021A>T · rs200063207 · VCV2350936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1719	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.39	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.084	GERP -2.2
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	10.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.045% European (non-Finnish) · 531/1,179,384 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.035% 564/1,612,914 alleles · ultra-rare exomes 545/1,461,022 · genomes 19/151,892 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.045%	2,221
Remaining individualsnot grpmax-eligible	0.0256%	3,902
Finnishnot grpmax-eligible	0.0188%	5,325
African / African-American	0.00535%	18,695
Admixed American	0.00167%	59,958

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.Ile341Phe
Coding: c.1021A>T
MANE Select: NM_024101
dbSNP: rs200063207
Type: single nucleotide variant
Location: chr2:237534564 (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.Ile341Asn Uncertain significance ★ ⚠ same residue
MLPH p.Ile341= Likely benign ★ same residue
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

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-ile341phe (accessed [today's date]).

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