Is MRTFA p.Pro444Leu (c.1331C>T) pathogenic?

MRTFA p.Pro444Leu (c.1331C>T) is classified Conflicting classifications of pathogenicity in MRTFA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.4393); Rare (popmax 0.195%, amr).

How common is MRTFA p.Pro444Leu (c.1331C>T) in the general population?

MRTFA p.Pro444Leu (c.1331C>T) is rare (popmax 0.195%, amr) (gnomAD).

What do computational predictors say about MRTFA p.Pro444Leu (c.1331C>T)?

AlphaMissense predicts ambiguous (score 0.4393) — an in-silico prediction, not a clinical call.

MRTFA p.Pro444Leu

c.1331C>T · rs142647978 · VCV1683088

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4393 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.195%, amr)

Computational evidence

Protein change
AlphaMissense	0.4393	ambiguous
REVEL	0.483	indeterminate
SaProt	LLR -14.95	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	30.0	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 P344L vs ClinVar P444L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.195% Admixed American · 117/60,006 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.0319% 515/1,613,626 alleles · rare exomes 461/1,461,238 · genomes 54/152,388 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.195%	513
Remaining individualsnot grpmax-eligible	0.0352%	2,841
European (non-Finnish)	0.0293%	3,410
South Asian	0.0231%	4,337
Middle Eastern	0.0165%	6,060
African / African-American	0.00666%	15,014
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00315%	31,778

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.Pro444Leu
Coding: c.1331C>T
MANE Select: NM_020831
dbSNP: rs142647978
Type: single nucleotide variant
Location: chr22:40420427 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 344 UniProt numbering: the 'disordered' region

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

Similar variants

MRTFA p.Pro444= Benign/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
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-pro444leu (accessed [today's date]).

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