Is MRTFA p.Arg660Gln (c.1979G>A) pathogenic?

MRTFA p.Arg660Gln (c.1979G>A) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.0807); Ultra-rare (popmax 0.0217%, mid).

How common is MRTFA p.Arg660Gln (c.1979G>A) in the general population?

MRTFA p.Arg660Gln (c.1979G>A) is ultra-rare (popmax 0.0217%, mid) (gnomAD).

What do computational predictors say about MRTFA p.Arg660Gln (c.1979G>A)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

MRTFA p.Arg660Gln

c.1979G>A · rs374264128 · VCV2414105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -6.87	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 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	25.9	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 R560Q vs ClinVar R660Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Middle Eastern · 1/4,602 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00222% 34/1,534,698 alleles · ultra-rare exomes 31/1,382,746 · genomes 3/151,952 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0217%	4,602
Ashkenazi Jewishnot grpmax-eligible	0.00363%	27,538
South Asian	0.0036%	27,746
Remaining individualsnot grpmax-eligible	0.00336%	29,803
East Asian	0.0024%	41,594
Finnishnot grpmax-eligible	0.00211%	47,458
European (non-Finnish)	0.00209%	47,791
Admixed American	0.002%	49,998

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.Arg660Gln
Coding: c.1979G>A
MANE Select: NM_020831
dbSNP: rs374264128
Type: single nucleotide variant
Location: chr22:40418759 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 560 UniProt numbering: the 'disordered' region

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

Similar variants

MRTFA p.Arg660Gly 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-arg660gln (accessed [today's date]).

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