Is MRTFA p.Arg650Gln (c.1949G>A) pathogenic?

MRTFA p.Arg650Gln (c.1949G>A) is classified Conflicting classifications of pathogenicity in MRTFA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.0655); Ultra-rare (popmax 0.0171%, nfe).

How common is MRTFA p.Arg650Gln (c.1949G>A) in the general population?

MRTFA p.Arg650Gln (c.1949G>A) is ultra-rare (popmax 0.0171%, nfe) (gnomAD).

What do computational predictors say about MRTFA p.Arg650Gln (c.1949G>A)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

MRTFA p.Arg650Gln

c.1949G>A · rs377354099 · VCV1683012

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.92	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 4.9	GERP 0.34, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	22.2	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 R550Q vs ClinVar R650Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0171% European (non-Finnish) · 200/1,171,650 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0144%

Overall 0.0154% 244/1,588,850 alleles · ultra-rare exomes 223/1,436,650 · genomes 21/152,200 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0308%	3,244
European (non-Finnish)grpmax	0.0171%	5,858
South Asian	0.0101%	9,866
African / African-American	0.0094%	10,634
East Asian	0.00912%	10,959
Admixed American	0.00521%	19,205
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,026
Finnishnot grpmax-eligible	0.0018%	55,434

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg650Gln
Coding: c.1949G>A
MANE Select: NM_020831
dbSNP: rs377354099
Type: single nucleotide variant
Location: chr22:40418789 (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.Arg650Leu Uncertain significance ★ ⚠ same residue
MRTFA p.Arg650Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg650gln (accessed [today's date]).

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