Is MYSM1 p.Leu289Phe (c.865C>T) pathogenic?

MYSM1 p.Leu289Phe (c.865C>T) is classified Likely benign in MYSM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0599); Ultra-rare (popmax 0.0493%, mid).

How common is MYSM1 p.Leu289Phe (c.865C>T) in the general population?

MYSM1 p.Leu289Phe (c.865C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about MYSM1 p.Leu289Phe (c.865C>T)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

MYSM1 p.Leu289Phe

c.865C>T · rs201666716 · VCV1130892

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -0.42, phastCons 0.95
Regional constraint	o/e 1.00	unconstrained · MANE · 28 kb · p 0.95 · regional, not allelic
Overall
CADD	14.36	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 0.0493% Middle Eastern · 3/6,082 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00889%

Overall 0.0151% 244/1,612,682 alleles · ultra-rare exomes 218/1,460,542 · genomes 26/152,140 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.308%	325
Middle Easterngrpmax	0.0493%	2,027
Remaining individualsnot grpmax-eligible	0.0256%	3,901
European (non-Finnish)	0.011%	9,069
Admixed American	0.00501%	19,980
African / African-American	0.00134%	74,864

Ashkenazi Jewish 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: MYSM1
Protein: p.Leu289Phe
Coding: c.865C>T
MANE Select: NM_001085487
dbSNP: rs201666716
Type: single nucleotide variant
Location: chr1:58682179 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.09 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.69 · 2 PDB

Full MYSM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MYSM1 p.Leu289= Likely benign ★ same residue
MYSM1 p.Arg506Ter Pathogenic ★★ same type
MYSM1 p.Gln629Ter Pathogenic ★★ same type
MYSM1 p.Arg138Gln Uncertain significance ★★ ⚠ same type
MYSM1 p.Arg150Cys Uncertain significance ★★ ⚠ same type
MYSM1 p.Arg204Cys Uncertain significance ★★ ⚠ same type
MYSM1 p.Arg478Gln Uncertain significance ★★ ⚠ same type
MYSM1 p.Arg494His 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/mysm1-p-leu289phe (accessed [today's date]).

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