Is MRTFA p.Arg476Cys (c.1426C>T) pathogenic?

MRTFA p.Arg476Cys (c.1426C>T) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9527); Very rare (popmax 0.00446%, eas).

How common is MRTFA p.Arg476Cys (c.1426C>T) in the general population?

MRTFA p.Arg476Cys (c.1426C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MRTFA p.Arg476Cys (c.1426C>T)?

AlphaMissense predicts likely pathogenic (score 0.9527) — an in-silico prediction, not a clinical call.

MRTFA p.Arg476Cys

c.1426C>T · VCV3696671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9527	likely pathogenic · top 10% in MRTFA
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -12.58	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 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	31.0	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 R376C vs ClinVar R476C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00161% 26/1,613,938 alleles · very rare exomes 24/1,461,652 · genomes 2/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
European (non-Finnish)	0.00203%	49,167

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.Arg476Cys
Coding: c.1426C>T
MANE Select: NM_020831
Type: single nucleotide variant
Location: chr22:40419312 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 376 UniProt numbering: the sap domain; an α-helix

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

Similar variants

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
MRTFA p.Ala616Val 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-arg476cys (accessed [today's date]).

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