Is MTF1 p.Pro443Ser (c.1327C>T) pathogenic?

MTF1 p.Pro443Ser (c.1327C>T) is classified Uncertain significance in MTF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely benign (0.0849); Very rare (popmax 0.00644%, nfe).

How common is MTF1 p.Pro443Ser (c.1327C>T) in the general population?

MTF1 p.Pro443Ser (c.1327C>T) is very rare (popmax 0.00644%, nfe) (gnomAD).

What do computational predictors say about MTF1 p.Pro443Ser (c.1327C>T)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

MTF1 p.Pro443Ser

c.1327C>T · rs375968162 · VCV2393405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -1.6, phastCons 1
Overall
CADD	19.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00644% European (non-Finnish) · 76/1,180,038 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00496% 80/1,614,002 alleles · very rare exomes 72/1,461,832 · genomes 8/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00644%	15,527
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed American	0.00167%	60,006
African / African-American	0.00134%	74,904

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.Pro443Ser
Coding: c.1327C>T
MANE Select: NM_005955
dbSNP: rs375968162
Type: single nucleotide variant
Location: chr1:37822561 (GRCh38)
Structure: AlphaFold pLDDT 89.80 · 1 PDB
Residue 443: the transferrin-like 2 domain

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

Similar variants

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
MELTF p.Asn135Ser Uncertain significance ★ ⚠ same type
MELTF p.Gln540Arg 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-pro443ser (accessed [today's date]).

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