Is MRTFA p.Pro734Leu (c.2201C>T) pathogenic?

MRTFA p.Pro734Leu (c.2201C>T) is classified Conflicting classifications of pathogenicity in MRTFA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0702); Very rare (popmax 0.00679%, afr).

How common is MRTFA p.Pro734Leu (c.2201C>T) in the general population?

MRTFA p.Pro734Leu (c.2201C>T) is very rare (popmax 0.00679%, afr) (gnomAD).

What do computational predictors say about MRTFA p.Pro734Leu (c.2201C>T)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

MRTFA p.Pro734Leu

c.2201C>T · rs747320600 · VCV1682985

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00679%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.03	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 1.1	GERP -4.3, phastCons 0.018
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	7.425	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 P634L vs ClinVar P734L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00679% African / African-American · 5/73,632 alleles

Filtering AF 0.00258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00158% 25/1,584,550 alleles · very rare exomes 22/1,432,442 · genomes 3/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00679%	14,726
Remaining individualsnot grpmax-eligible	0.00491%	20,355
South Asian	0.0023%	43,408
East Asian	0.00223%	44,764
Admixed American	0.00193%	51,916
European (non-Finnish)	0.00111%	89,958

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.Pro734Leu
Coding: c.2201C>T
MANE Select: NM_020831
dbSNP: rs747320600
Type: single nucleotide variant
Location: chr22:40418537 (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.Pro734= Likely benign ★★ same residue
MRTFA p.Pro734Ser Benign ★★ same residue
MRTFA p.Pro734Ala 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

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-pro734leu (accessed [today's date]).

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