Is TMPRSS6 p.Pro320Thr (c.958C>A) pathogenic?

TMPRSS6 p.Pro320Thr (c.958C>A) is classified Uncertain significance in TMPRSS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). AlphaMissense: likely benign (0.1062); Ultra-rare (popmax 0.0694%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS6 p.Pro320Thr (c.958C>A)?

TMPRSS6 p.Pro320Thr (c.958C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS6 p.Pro320Thr (c.958C>A) in the general population?

TMPRSS6 p.Pro320Thr (c.958C>A) is ultra-rare (popmax 0.0694%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Pro320Thr (c.958C>A)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Pro320Thr

c.958C>A · rs138251339 · VCV1300922

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0694%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -4.59	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 0.001	GERP -2.9, phastCons 0.35
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	13.51	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P329T vs ClinVar P320T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0694% African / African-American · 52/74,976 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0489%

Overall 0.00415% 67/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0694%	1,442
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00666%	15,006
South Asian	0.00329%	30,361
European (non-Finnish)	0.000254%	393,331

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.Pro320Thr
Coding: c.958C>A
MANE Select: NM_001374504
dbSNP: rs138251339
Type: single nucleotide variant
Location: chr22:37086298 (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 320: the cub 1 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.Pro320= Benign/Likely benign ★★ same residue
TMPRSS6 p.Pro320Leu Uncertain significance ★ ⚠ same residue
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

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-pro320thr (accessed [today's date]).

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