Is MRTFA p.Arg409Cys (c.1225C>T) pathogenic?

MRTFA p.Arg409Cys (c.1225C>T) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.1059); Ultra-rare (popmax 0.0497%, mid).

How common is MRTFA p.Arg409Cys (c.1225C>T) in the general population?

MRTFA p.Arg409Cys (c.1225C>T) is ultra-rare (popmax 0.0497%, mid) (gnomAD).

What do computational predictors say about MRTFA p.Arg409Cys (c.1225C>T)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

MRTFA p.Arg409Cys

c.1225C>T · rs149876356 · VCV1683104

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0497%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -9.25	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 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	23.8	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 R309C vs ClinVar R409C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0497% Middle Eastern · 3/6,032 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0123%

Overall 0.013% 210/1,613,708 alleles · ultra-rare exomes 196/1,461,328 · genomes 14/152,380 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0497%	2,011
Remaining individualsnot grpmax-eligible	0.0256%	3,906
East Asian	0.0156%	6,413
European (non-Finnish)	0.0147%	6,782
African / African-American	0.00799%	12,512
South Asian	0.00439%	22,772

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: MRTFA
Protein: p.Arg409Cys
Coding: c.1225C>T
MANE Select: NM_020831
dbSNP: rs149876356
Type: single nucleotide variant
Location: chr22:40420533 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 309 UniProt numbering: the 'disordered' region

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

Similar variants

MRTFA p.Arg409His Uncertain significance ★ ⚠ same residue
MRTFA p.Ala352Thr Uncertain significance ★★ ⚠ same type
MRTFA p.Ala360Thr Uncertain significance ★★ ⚠ same type
MRTFA p.Ala429Ser Uncertain significance ★★ ⚠ same type
MRTFA p.Ala479Gly Uncertain significance ★★ ⚠ same type
MRTFA p.Ala479Val Uncertain significance ★★ ⚠ same type
MRTFA p.Ala534Thr Uncertain significance ★★ ⚠ same type
MRTFA p.Ala537Val 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/mrtfa-p-arg409cys (accessed [today's date]).

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