Is SHBG p.Pro35Ser (c.103C>T) pathogenic?

SHBG p.Pro35Ser (c.103C>T) is classified Uncertain significance in SHBG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0825); Very rare (popmax 0.00401%, afr).

How common is SHBG p.Pro35Ser (c.103C>T) in the general population?

SHBG p.Pro35Ser (c.103C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about SHBG p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

SHBG p.Pro35Ser

c.103C>T · VCV4164574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -6.93	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 0.19	GERP 0.13
Regional constraint	o/e 0.93	unconstrained · MANE · 3,176 bp · p 0.13 · regional, not allelic
Overall
CADD	9.947	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 0.00401% African / African-American · 3/74,728 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000187% 3/1,607,856 alleles · very rare exomes 1/1,455,678 · genomes 2/152,178 · 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: SHBG
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_001040
Type: single nucleotide variant
Location: chr17:7630275 (GRCh38)
Gene constraint: LOEUF 1.096 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.03 · 13 PDB

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

Similar variants

SHBG p.Ala179Pro Benign ★★ same type
SHBG p.Arg25His Benign ★★ same type
SHBG p.Arg314= Benign ★★ same type
SHBG p.Asp356Asn Benign ★★ same type
SHBG p.His40= Benign ★★ same type
SHBG p.Ala114Val Uncertain significance ★ ⚠ same type
SHBG p.Ala325Asp Uncertain significance ★ ⚠ same type
SHBG p.Ala39Thr 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/shbg-p-pro35ser (accessed [today's date]).

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