Is TMPRSS6 p.Arg789Pro (c.2366G>C) pathogenic?

TMPRSS6 p.Arg789Pro (c.2366G>C) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.98); Absent from gnomAD v4.1.

How common is TMPRSS6 p.Arg789Pro (c.2366G>C) in the general population?

TMPRSS6 p.Arg789Pro (c.2366G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS6 p.Arg789Pro (c.2366G>C)?

AlphaMissense predicts likely pathogenic (score 0.98) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Arg789Pro

c.2366G>C · VCV3720220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.98 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.98	likely pathogenic · top 5% in TMPRSS6
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.97, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R798P vs ClinVar R789P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPRSS6
Protein: p.Arg789Pro
Coding: c.2366G>C
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37066123 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.69 · 1 PDB
Residue 789: the peptidase s1 domain

Full TMPRSS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS6 p.Arg789Cys Uncertain significance ★ ⚠ same residue
TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same type
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same type
TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same type
TMPRSS6 p.Lys70Ter Likely pathogenic ★★ same type
TMPRSS6 p.Ser552Ter Pathogenic ★★ same type
TMPRSS6 p.Tyr346Ter Likely pathogenic ★★ 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/tmprss6-p-arg789pro (accessed [today's date]).

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