Is MRTFA p.Pro344Leu (c.1031C>T) pathogenic?

MRTFA p.Pro344Leu (c.1031C>T) is classified Uncertain significance in MRTFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.9209); Very rare (popmax 0.00222%, sas).

How common is MRTFA p.Pro344Leu (c.1031C>T) in the general population?

MRTFA p.Pro344Leu (c.1031C>T) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about MRTFA p.Pro344Leu (c.1031C>T)?

AlphaMissense predicts likely pathogenic (score 0.9209) — an in-silico prediction, not a clinical call.

MRTFA p.Pro344Leu

c.1031C>T · VCV4553404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9209	likely pathogenic
REVEL	0.628	indeterminate
SaProt	LLR -12.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	32.0	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 P244L vs ClinVar P344L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00222% South Asian · 2/90,184 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000374% 6/1,605,866 alleles · very rare exomes 6/1,453,514 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,092
European (non-Finnish)	0.000341%	293,639

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.Pro344Leu
Coding: c.1031C>T
MANE Select: NM_020831
Type: single nucleotide variant
Location: chr22:40420997 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 244 UniProt numbering: the 'mediates interaction with scai and actb' region; the 'disordered' region

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

Similar variants

MRTFA p.Pro344Arg Uncertain significance ★ ⚠ same residue
MRTFA p.Pro344= 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
MRTFA p.Ala534Thr 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-pro344leu (accessed [today's date]).

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