Is MRTFA p.Ser592Leu (c.1775C>T) pathogenic?

MRTFA p.Ser592Leu (c.1775C>T) is classified Uncertain significance in MRTFA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: ambiguous (0.3609); Ultra-rare (popmax 0.0329%, mid).

How common is MRTFA p.Ser592Leu (c.1775C>T) in the general population?

MRTFA p.Ser592Leu (c.1775C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about MRTFA p.Ser592Leu (c.1775C>T)?

AlphaMissense predicts ambiguous (score 0.3609) — an in-silico prediction, not a clinical call.

MRTFA p.Ser592Leu

c.1775C>T · VCV3699427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3609 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Computational evidence

Protein change
AlphaMissense	0.3609	ambiguous
REVEL	0.352	indeterminate
SaProt	LLR -7.13	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	29.5	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 S492L vs ClinVar S592L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00118% 19/1,612,768 alleles · ultra-rare exomes 18/1,460,580 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
East Asian	0.00223%	44,882
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.00119%	84,282

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.Ser592Leu
Coding: c.1775C>T
MANE Select: NM_020831
Type: single nucleotide variant
Location: chr22:40418963 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 492 UniProt numbering: a modified residue (phosphoserine)

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

Similar variants

MRTFA p.Ser592= Likely benign ★★ same residue
MRTFA p.Ser592Pro 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

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-ser592leu (accessed [today's date]).

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