Is TMPRSS6 p.Ser552Leu (c.1655C>T) pathogenic?

TMPRSS6 p.Ser552Leu (c.1655C>T) is classified Uncertain significance in TMPRSS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-22). AlphaMissense: ambiguous (0.3512); Very rare (popmax 0.00271%, nfe); Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Ser552Leu (c.1655C>T)?

TMPRSS6 p.Ser552Leu (c.1655C>T) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Ser552Leu (c.1655C>T) in the general population?

TMPRSS6 p.Ser552Leu (c.1655C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

How is IRIDA syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMPRSS6 p.Ser552Leu (c.1655C>T)?

AlphaMissense predicts ambiguous (score 0.3512) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Ser552Leu

c.1655C>T · rs143441292 · VCV3179932

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

IRIDA syndrome

Computational evidence

Protein change
AlphaMissense	0.3512	ambiguous
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S561L vs ClinVar S552L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% European (non-Finnish) · 32/1,179,998 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00236% 38/1,613,012 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,821
European (non-Finnish)grpmax	0.00271%	36,875
African / African-American	0.00267%	37,447
East Asian	0.00223%	44,884

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser552Leu
Coding: c.1655C>T
MANE Select: NM_001374504
dbSNP: rs143441292
Type: single nucleotide variant
Location: chr22:37070933 (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 552: a β-strand; a disulfide bond; the ldl-receptor class a 3 domain

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

Disease context

IRIDA syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For IRIDA syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS6 p.Ser552Ter Pathogenic ★★ same residue
TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same condition
TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMPRSS6 p.Tyr346Ter Likely pathogenic ★★ same condition
TMPRSS6 p.Arg88Cys Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Asp466Asn 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-ser552leu (accessed [today's date]).

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