Is MRTFA p.Pro593Thr (c.1777C>A) pathogenic?

MRTFA p.Pro593Thr (c.1777C>A) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.3694); Very rare (popmax 0.00347%, nfe).

How common is MRTFA p.Pro593Thr (c.1777C>A) in the general population?

MRTFA p.Pro593Thr (c.1777C>A) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about MRTFA p.Pro593Thr (c.1777C>A)?

AlphaMissense predicts ambiguous (score 0.3694) — an in-silico prediction, not a clinical call.

MRTFA p.Pro593Thr

c.1777C>A · rs200565523 · VCV1337929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3694	ambiguous
REVEL	0.417	indeterminate
SaProt	LLR -7.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	26.1	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 P493T vs ClinVar P593T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,179,950 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00341% 55/1,612,794 alleles · very rare exomes 54/1,460,590 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0192%	5,205
European (non-Finnish)grpmax	0.00347%	28,779
Finnishnot grpmax-eligible	0.00318%	31,453

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.Pro593Thr
Coding: c.1777C>A
MANE Select: NM_020831
dbSNP: rs200565523
Type: single nucleotide variant
Location: chr22:40418961 (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.Pro593Ser 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-pro593thr (accessed [today's date]).

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