Is SON p.Gln45Pro (c.134A>C) pathogenic?

SON p.Gln45Pro (c.134A>C) is classified Uncertain significance in SON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-14). AlphaMissense: likely benign (0.0919); Ultra-rare (popmax 0.01%, amr); Associated with SON-related disorder.

What condition is associated with SON p.Gln45Pro (c.134A>C)?

SON p.Gln45Pro (c.134A>C) is associated with SON-related disorder (ClinVar).

How common is SON p.Gln45Pro (c.134A>C) in the general population?

SON p.Gln45Pro (c.134A>C) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about SON p.Gln45Pro (c.134A>C)?

AlphaMissense predicts likely benign (score 0.0919) — an in-silico prediction, not a clinical call.

SON p.Gln45Pro

c.134A>C · rs775890214 · VCV2636632

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0919 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SON-related disorder

Computational evidence

Protein change
AlphaMissense	0.0919	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.48	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 7.8	GERP 3.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	21.2	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 0.01% Admixed American · 6/59,980 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000744% 12/1,613,824 alleles · ultra-rare exomes 9/1,461,606 · genomes 3/152,218 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,997
European (non-Finnish)	0.000509%	196,649

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: SON
Protein: p.Gln45Pro
Coding: c.134A>C
MANE Select: NM_138927
dbSNP: rs775890214
Type: single nucleotide variant
Location: chr21:33546269 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 45: the 'disordered' region

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

Disease context

SON-related disorder

Similar variants

SON p.Leu1666Val Uncertain significance ★★ ⚠ same condition
SON p.Pro431His Uncertain significance ★★ ⚠ same condition
SON p.Ser609Leu Uncertain significance ★★ ⚠ same condition
SON p.Thr1382Ser Uncertain significance ★★ ⚠ same condition
SON p.Arg1956His Likely pathogenic ★ ⚠ same condition
SON p.Gln228Ter Likely pathogenic ★ same condition
SON p.Gln918Ter Pathogenic ★ same condition
SON p.Glu363Ter Likely 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/son-p-gln45pro (accessed [today's date]).

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