Is MRTFA p.Pro406His (c.1217C>A) pathogenic?

MRTFA p.Pro406His (c.1217C>A) is classified Conflicting classifications of pathogenicity in MRTFA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.098); Rare (popmax 0.425%, afr).

How common is MRTFA p.Pro406His (c.1217C>A) in the general population?

MRTFA p.Pro406His (c.1217C>A) is rare (popmax 0.425%, afr) (gnomAD).

What do computational predictors say about MRTFA p.Pro406His (c.1217C>A)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

MRTFA p.Pro406His

c.1217C>A · rs144872390 · VCV777725

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.425%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -7.84	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	23.3	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 P306H vs ClinVar P406H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.425% African / African-American · 319/75,062 alleles

Filtering AF 0.387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.0211% 340/1,613,656 alleles · rare exomes 145/1,461,284 · genomes 195/152,372 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.425%	235
Admixed American	0.0167%	6,004
Remaining individualsnot grpmax-eligible	0.016%	6,249
South Asian	0.0011%	91,080

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.Pro406His
Coding: c.1217C>A
MANE Select: NM_020831
dbSNP: rs144872390
Type: single nucleotide variant
Location: chr22:40420541 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.59 · 2 PDB
Residue 306 UniProt numbering: the 'disordered' region

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

Similar variants

MRTFA p.Pro406Leu Uncertain significance ★ ⚠ same residue
MRTFA p.Pro406Thr Uncertain significance ★ ⚠ same residue
MRTFA p.Pro406Ala 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

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-pro406his (accessed [today's date]).

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