Is MYL4 p.Pro103Ser (c.307C>T) pathogenic?

MYL4 p.Pro103Ser (c.307C>T) is classified Uncertain significance in MYL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-23). AlphaMissense: likely benign (0.1617); Very rare (popmax 0.00133%, afr); Associated with atrial fibrillation, familial, 18.

What condition is associated with MYL4 p.Pro103Ser (c.307C>T)?

MYL4 p.Pro103Ser (c.307C>T) is associated with atrial fibrillation, familial, 18 (ClinVar).

How common is MYL4 p.Pro103Ser (c.307C>T) in the general population?

MYL4 p.Pro103Ser (c.307C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Hereditary atrial fibrillation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MYL4 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely benign (score 0.1617) — an in-silico prediction, not a clinical call.

MYL4 p.Pro103Ser

c.307C>T · VCV3689698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atrial fibrillation, familial, 18

Computational evidence

Protein change
AlphaMissense	0.1617	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP 0.89, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.81 · regional, not allelic
Overall
CADD	16.45	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 0.00133% African / African-American · 1/75,054 alleles

Overall 6.2e-05% 1/1,612,706 alleles · very rare exomes 1/1,460,334 · genomes 0/152,372 · joint denominator

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: MYL4
Protein: p.Pro103Ser
Coding: c.307C>T
MANE Select: NM_002476
Type: single nucleotide variant
Location: chr17:47220047 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.85

Full MYL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atrial fibrillation, familial, 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary atrial fibrillation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

MYL4 p.Ala84Val Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg125Cys Uncertain significance ★★ same condition
MYL4 p.Arg125His Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg140His Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg156Gln Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg156Trp Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg65Gln Uncertain significance ★★ ⚠ same condition
MYL4 p.Arg83Trp 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/myl4-p-pro103ser (accessed [today's date]).

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