Is TMPRSS6 p.Val481Ile (c.1441G>A) pathogenic?

TMPRSS6 p.Val481Ile (c.1441G>A) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-15). AlphaMissense: likely benign (0.1003); Rare (popmax 0.164%, mid).

How common is TMPRSS6 p.Val481Ile (c.1441G>A) in the general population?

TMPRSS6 p.Val481Ile (c.1441G>A) is rare (popmax 0.164%, mid) (gnomAD).

What do computational predictors say about TMPRSS6 p.Val481Ile (c.1441G>A)?

AlphaMissense predicts likely benign (score 0.1003) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Val481Ile

c.1441G>A · VCV4753866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1003 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1003	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -5.04	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 5.8	GERP 0.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	33.0	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 V490I vs ClinVar V481I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.164% Middle Eastern · 10/6,082 alleles

Filtering AF 0.0891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0679%

Overall 0.00446% 72/1,613,942 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.164%	608
South Asian	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.00398%	25,105
Admixed American	0.00333%	29,998
African / African-American	0.00267%	37,457

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.Val481Ile
Coding: c.1441G>A
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37074610 (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 481: a disulfide bond; the ldl-receptor class a 1 domain

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

Similar variants

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
TMPRSS6 p.Ala164Thr 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/tmprss6-p-val481ile (accessed [today's date]).

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