Is DMTF1 p.Pro619Leu (c.1856C>T) pathogenic?

DMTF1 p.Pro619Leu (c.1856C>T) is classified Uncertain significance in DMTF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0925); Ultra-rare (popmax 0.033%, mid).

How common is DMTF1 p.Pro619Leu (c.1856C>T) in the general population?

DMTF1 p.Pro619Leu (c.1856C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about DMTF1 p.Pro619Leu (c.1856C>T)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

DMTF1 p.Pro619Leu

c.1856C>T · VCV4241548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.21	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 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,032 bp · p 0.62 · regional, not allelic
Overall
CADD	23.1	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 0.033% Middle Eastern · 2/6,052 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000753% 11/1,461,220 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,026
Remaining individualsnot grpmax-eligible	0.0032%	31,235
South Asian	0.0011%	91,066
European (non-Finnish)	0.000509%	196,601

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: DMTF1
Protein: p.Pro619Leu
Coding: c.1856C>T
MANE Select: NM_001142327
Type: single nucleotide variant
Location: chr7:87193930 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.72 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 1 PDB
Residue 619: the 'required for transcriptional activation' region; the 'interaction with ccnd1, ccnd2 and ccnd3' region

Full DMTF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DMTF1 p.Pro619Arg Uncertain significance ★ ⚠ same residue
DMP1 p.Gly135Ter Pathogenic/Likely pathogenic ★★ same type
DMP1 p.Met1Val Pathogenic/Likely pathogenic ★★ same type
DMP1 c.*159T>A Uncertain significance ★★ same type
DMP1 c.*77T>C Uncertain significance ★★ same type
DMP1 p.Arg173Trp Uncertain significance ★★ ⚠ same type
DMP1 p.Arg302Ile Uncertain significance ★★ ⚠ same type
DMP1 p.Arg310Lys 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/dmtf1-p-pro619leu (accessed [today's date]).

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