Is MRTFA p.Val768Ala (c.2303T>C) pathogenic?

MRTFA p.Val768Ala (c.2303T>C) is classified Uncertain significance in MRTFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.3841); Ultra-rare (popmax 0.0822%, mid).

How common is MRTFA p.Val768Ala (c.2303T>C) in the general population?

MRTFA p.Val768Ala (c.2303T>C) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about MRTFA p.Val768Ala (c.2303T>C)?

AlphaMissense predicts ambiguous (score 0.3841) — an in-silico prediction, not a clinical call.

MRTFA p.Val768Ala

c.2303T>C · rs748217781 · VCV1682972

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3841	ambiguous
REVEL	0.057	moderately benign-leaning
SaProt	LLR -8.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.043 · regional, not allelic
Overall
CADD	20.4	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 V668A vs ClinVar V768A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0822% Middle Eastern · 5/6,080 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00149% 24/1,613,804 alleles · ultra-rare exomes 23/1,461,766 · genomes 1/152,038 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
South Asian	0.00439%	22,770
African / African-American	0.00401%	24,953
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000848%	117,993

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.Val768Ala
Coding: c.2303T>C
MANE Select: NM_020831
dbSNP: rs748217781
Type: single nucleotide variant
Location: chr22:40418435 (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.Val768= 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-val768ala (accessed [today's date]).

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