Is MRTFA p.Arg650Trp (c.1948C>T) pathogenic?

MRTFA p.Arg650Trp (c.1948C>T) is classified Conflicting classifications of pathogenicity in MRTFA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.00786%, sas).

How common is MRTFA p.Arg650Trp (c.1948C>T) in the general population?

MRTFA p.Arg650Trp (c.1948C>T) is very rare (popmax 0.00786%, sas) (gnomAD).

What do computational predictors say about MRTFA p.Arg650Trp (c.1948C>T)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

MRTFA p.Arg650Trp

c.1948C>T · rs780789822 · VCV1040924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00786%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -10.65	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -4.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R550W vs ClinVar R650W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00786% South Asian · 7/89,004 alleles

Filtering AF 0.00366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00088% 14/1,591,230 alleles · very rare exomes 14/1,439,004 · genomes 0/152,226 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00786%	12,715
African / African-American	0.00134%	74,522
European (non-Finnish)	0.000512%	195,472

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.Arg650Trp
Coding: c.1948C>T
MANE Select: NM_020831
dbSNP: rs780789822
Type: single nucleotide variant
Location: chr22:40418790 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB

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

Similar variants

MRTFA p.Arg650Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MRTFA p.Arg650Leu Uncertain significance ★ ⚠ same residue
MRTFA p.Arg650= Likely benign ★ 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

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-arg650trp (accessed [today's date]).

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