Is STH p.Ser2Ile (c.5G>T) pathogenic?

STH p.Ser2Ile (c.5G>T) is classified Uncertain significance in STH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-09). AlphaMissense: likely benign (0.1944); Very rare (popmax 0.00102%, nfe).

How common is STH p.Ser2Ile (c.5G>T) in the general population?

STH p.Ser2Ile (c.5G>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about STH p.Ser2Ile (c.5G>T)?

AlphaMissense predicts likely benign (score 0.1944) — an in-silico prediction, not a clinical call.

STH p.Ser2Ile

c.5G>T · rs780674994 · VCV2397123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1944	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -1.6
Regional constraint	o/e 0.73	unconstrained · MANE · 155 bp · p 0.032 · regional, not allelic
Overall
CADD	0.671	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 0.00102% European (non-Finnish) · 12/1,179,500 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000744% 12/1,612,906 alleles · very rare exomes 11/1,460,674 · genomes 1/152,232 · joint denominator

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: STH
Protein: p.Ser2Ile
Coding: c.5G>T
MANE Select: NM_001007532
dbSNP: rs780674994
Type: single nucleotide variant
Location: chr17:45999284 (GRCh38)
Gene constraint: LOEUF 1.954 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 57.88

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

Similar variants

STH p.Ala112Asp Uncertain significance ★ ⚠ same type
STH p.Asp45Val Uncertain significance ★ same type
STH p.Gln93Lys Uncertain significance ★ ⚠ same type
STH p.Gly119Arg Uncertain significance ★ ⚠ same type
STH p.Met39Ile Uncertain significance ★ ⚠ same type
STH p.Pro109Arg Uncertain significance ★ ⚠ same type
STH p.Pro116Thr Uncertain significance ★ ⚠ same type
STH p.Pro22Leu 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/sth-p-ser2ile (accessed [today's date]).

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