Is MTDH p.Arg207Cys (c.619C>T) pathogenic?

MTDH p.Arg207Cys (c.619C>T) is classified Uncertain significance in MTDH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely pathogenic (0.9259); Very rare (popmax 0.00168%, amr).

How common is MTDH p.Arg207Cys (c.619C>T) in the general population?

MTDH p.Arg207Cys (c.619C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about MTDH p.Arg207Cys (c.619C>T)?

AlphaMissense predicts likely pathogenic (score 0.9259) — an in-silico prediction, not a clinical call.

MTDH p.Arg207Cys

c.619C>T · rs1242588795 · VCV3214187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9259	likely pathogenic · top 9% in MTDH
REVEL	0.274	benign-leaning
SaProt	LLR -11.94	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 55 kb · p 0.92 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,650 alleles

Overall 6.2e-05% 1/1,611,860 alleles · very rare exomes 1/1,459,738 · genomes 0/152,122 · joint denominator

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: MTDH
Protein: p.Arg207Cys
Coding: c.619C>T
MANE Select: NM_178812
dbSNP: rs1242588795
Type: single nucleotide variant
Location: chr8:97687479 (GRCh38)
Gene constraint: LOEUF 0.535 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 51.96 · 1 PDB
Residue 207: the 'disordered' region

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

Similar variants

MTDH p.Val54Met Benign/Likely benign ★★ same type
MTDH p.Ala136Thr Uncertain significance ★ ⚠ same type
MTDH p.Ala136Val Uncertain significance ★ ⚠ same type
MTDH p.Ala238Thr Uncertain significance ★ ⚠ same type
MTDH p.Ala329Ser Uncertain significance ★ ⚠ same type
MTDH p.Ala72Val Uncertain significance ★ ⚠ same type
MTDH p.Ala94Gly Uncertain significance ★ ⚠ same type
MTDH p.Ala94Val 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/mtdh-p-arg207cys (accessed [today's date]).

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