Is MYO7B p.Leu1522Pro (c.4565T>C) pathogenic?

MYO7B p.Leu1522Pro (c.4565T>C) is classified Uncertain significance in MYO7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.8007); Very rare (popmax 0.00388%, amr).

How common is MYO7B p.Leu1522Pro (c.4565T>C) in the general population?

MYO7B p.Leu1522Pro (c.4565T>C) is very rare (popmax 0.00388%, amr) (gnomAD).

What do computational predictors say about MYO7B p.Leu1522Pro (c.4565T>C)?

AlphaMissense predicts likely pathogenic (score 0.8007) — an in-silico prediction, not a clinical call.

MYO7B p.Leu1522Pro

c.4565T>C · VCV4115771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00388%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8007	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -12.47	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 69 kb · p 0.0075 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 L1496P vs ClinVar L1522P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00388% Admixed American · 2/51,592 alleles

Filtering AF 0.000643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000241%

Overall 0.000193% 3/1,554,852 alleles · very rare exomes 3/1,405,106 · genomes 0/149,746 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00388%	25,796
European (non-Finnish)	8.69e-05%	1,150,579

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.Leu1522Pro
Coding: c.4565T>C
MANE Select: NM_001393586
Type: single nucleotide variant
Location: chr2:127628476 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.34 · 3 PDB
Residue 1496 UniProt numbering: the 'mediates interaction with anks4b' region; the ferm 1 domain

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

Similar variants

MYO7B p.Thr349Met Uncertain significance ★★ ⚠ same type
MYO7B p.Ile1309Val Benign ★★ same type
MYO7B p.Val1556Ile Benign ★★ same type
MYO7B p.Val1876= Benign ★★ same type
MYO7B p.Ala1010Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1092Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1109Thr Uncertain significance ★ ⚠ same type
MYO7B p.Ala1126Thr 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/myo7b-p-leu1522pro (accessed [today's date]).

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