Is MYO7B p.Leu1991Phe (c.5971C>T) pathogenic?

MYO7B p.Leu1991Phe (c.5971C>T) is classified Uncertain significance in MYO7B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely benign (0.0974); Ultra-rare (popmax 0.0508%, amr).

How common is MYO7B p.Leu1991Phe (c.5971C>T) in the general population?

MYO7B p.Leu1991Phe (c.5971C>T) is ultra-rare (popmax 0.0508%, amr) (gnomAD).

What do computational predictors say about MYO7B p.Leu1991Phe (c.5971C>T)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

MYO7B p.Leu1991Phe

c.5971C>T · VCV3401655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.33	GERP -0.54, phastCons 0.75
Regional constraint	o/e 1.07	unconstrained · MANE · 7,741 bp · p 0.063 · regional, not allelic
Overall
CADD	20.9	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L1965F vs ClinVar L1991F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0508% Admixed American · 28/55,142 alleles

Filtering AF 0.0361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00424% 67/1,581,752 alleles · ultra-rare exomes 50/1,429,434 · genomes 17/152,318 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0508%	1,969
Remaining individualsnot grpmax-eligible	0.00326%	30,674
European (non-Finnish)	0.00309%	32,346
African / African-American	0.00135%	74,170

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: MYO7B
Protein: p.Leu1991Phe
Coding: c.5971C>T
MANE Select: NM_001393586
Type: single nucleotide variant
Location: chr2:127635872 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.34 · 3 PDB
Residue 1965 UniProt numbering: the ferm 2 domain; the 'mediates interaction with cdhr2, cdhr5 and ush1c' region; a turn

Full MYO7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/myo7b-p-leu1991phe (accessed [today's date]).

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