Is TMPRSS6 p.Glu637Asp (c.1911G>C) pathogenic?

TMPRSS6 p.Glu637Asp (c.1911G>C) is classified Uncertain significance in TMPRSS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.6886); Ultra-rare (popmax 0.0384%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS6 p.Glu637Asp (c.1911G>C)?

TMPRSS6 p.Glu637Asp (c.1911G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS6 p.Glu637Asp (c.1911G>C) in the general population?

TMPRSS6 p.Glu637Asp (c.1911G>C) is ultra-rare (popmax 0.0384%, amr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Glu637Asp (c.1911G>C)?

AlphaMissense predicts likely pathogenic (score 0.6886) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Glu637Asp

c.1911G>C · VCV3388441

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6886	likely pathogenic
REVEL	0.519	indeterminate
SaProt	LLR -13.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	25.4	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 E646D vs ClinVar E637D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0384% Admixed American · 23/59,820 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00143% 23/1,611,042 alleles · ultra-rare

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: TMPRSS6
Protein: p.Glu637Asp
Coding: c.1911G>C
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37069275 (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 637: the peptidase s1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS6 p.Ala164Thr Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg121His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg251Gln Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg545Trp Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg780Gln Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg96His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Asp600Val Uncertain significance ★★ ⚠ same condition

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-glu637asp (accessed [today's date]).

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