Is MTF1 p.Pro408= (c.1224G>A) pathogenic?

MTF1 p.Pro408= (c.1224G>A) is classified Likely benign in MTF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Ultra-rare (popmax 0.0602%, eas).

How common is MTF1 p.Pro408= (c.1224G>A) in the general population?

MTF1 p.Pro408= (c.1224G>A) is ultra-rare (popmax 0.0602%, eas) (gnomAD).

MTF1 p.Pro408=

c.1224G>A · rs140764958 · VCV730186

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0602%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.1	GERP -3.7
Overall
CADD	7.864	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0602% East Asian · 27/44,878 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00911% 147/1,613,452 alleles · ultra-rare exomes 116/1,461,370 · genomes 31/152,082 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.122%	822
East Asiangrpmax	0.0602%	1,662
African / African-American	0.0307%	3,259
Admixed American	0.0167%	5,999
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.00157%	63,520
European (non-Finnish)	0.000763%	131,107

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: MTF1
Protein: p.Pro408=
Coding: c.1224G>A
MANE Select: NM_005955
dbSNP: rs140764958
Type: single nucleotide variant
Location: chr1:37822664 (GRCh38)
Structure: AlphaFold pLDDT 89.80 · 1 PDB
Residue 408: the transferrin-like 2 domain; an α-helix

Full MTF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTF1 p.Pro408Ala Uncertain significance ★ ⚠ same residue
MTF1 p.Pro408Leu Uncertain significance ★ ⚠ same residue
MELTF p.Val55Ile Benign ★★ same type
MTF1 p.Thr228= Likely benign ★★ same type
MTF1 p.Thr364Ile Likely benign ★★ same type
MELTF p.Ala699Val Uncertain significance ★ ⚠ same type
MELTF p.Arg215Trp Uncertain significance ★ ⚠ same type
MELTF p.Arg275Gln 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/mtf1-p-pro408 (accessed [today's date]).

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