Is SECISBP2 p.Ser592Leu (c.1775C>T) pathogenic?

SECISBP2 p.Ser592Leu (c.1775C>T) is classified Uncertain significance in SECISBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-24). AlphaMissense: likely benign (0.0598); Very rare (popmax 0.004%, afr); Associated with thyroid hormone metabolism, abnormal 1.

What condition is associated with SECISBP2 p.Ser592Leu (c.1775C>T)?

SECISBP2 p.Ser592Leu (c.1775C>T) is associated with thyroid hormone metabolism, abnormal 1 (ClinVar).

How common is SECISBP2 p.Ser592Leu (c.1775C>T) in the general population?

SECISBP2 p.Ser592Leu (c.1775C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about SECISBP2 p.Ser592Leu (c.1775C>T)?

AlphaMissense predicts likely benign (score 0.0598) — an in-silico prediction, not a clinical call.

SECISBP2 p.Ser592Leu

Q: How is Short stature-delayed bone age due to thyroid hormone metabolism deficiency inherited?

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

c.1775C>T · rs187624831 · VCV2435802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid hormone metabolism, abnormal 1

Computational evidence

Protein change
AlphaMissense	0.0598	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.5	GERP -3
Regional constraint	o/e 1.02	unconstrained · MANE · 40 kb · p 0.47 · regional, not allelic
Overall
CADD	0.353	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,022 alleles

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

Overall 0.00836% 135/1,614,168 alleles · very rare exomes 121/1,461,894 · genomes 14/152,274 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.141%	711
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-Americangrpmax	0.004%	25,007
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.00271%	36,876
South Asian	0.0011%	91,072

Finnish 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: SECISBP2
Protein: p.Ser592Leu
Coding: c.1775C>T
MANE Select: NM_024077
dbSNP: rs187624831
Type: single nucleotide variant
Location: chr9:89349812 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.54 · 2 PDB
Residue 592: the 'disordered' region

Full SECISBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thyroid hormone metabolism, abnormal 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Short stature-delayed bone age due to thyroid hormone metabolism deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

SECISBP2 c.1089+2T>C Pathogenic ★ same condition
SECISBP2 c.182+1G>A Likely pathogenic ★ same condition
SECISBP2 p.Arg120Ter Pathogenic ★ same condition
SECISBP2 p.Arg672Ter Likely pathogenic ★ same condition
SECISBP2 p.Arg770Ter Pathogenic ★ same condition
SECISBP2 p.Lys774Ter Uncertain significance ★ same condition
SECISBP2 p.Ser46Cys Uncertain significance ★ ⚠ same condition
SECISBP2 c.1212+29G>A Pathogenic 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/secisbp2-p-ser592leu (accessed [today's date]).

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