Is SON p.Pro454Arg (c.1361C>G) pathogenic?

SON p.Pro454Arg (c.1361C>G) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.1636); Ultra-rare (popmax 0.0588%, afr); Associated with Inborn genetic diseases.

What condition is associated with SON p.Pro454Arg (c.1361C>G)?

SON p.Pro454Arg (c.1361C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SON p.Pro454Arg (c.1361C>G) in the general population?

SON p.Pro454Arg (c.1361C>G) is ultra-rare (popmax 0.0588%, afr) (gnomAD).

What do computational predictors say about SON p.Pro454Arg (c.1361C>G)?

AlphaMissense predicts likely benign (score 0.1636) — an in-silico prediction, not a clinical call.

SON p.Pro454Arg

c.1361C>G · rs372024048 · VCV2172544

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0588%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1636	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 4.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0588% African / African-American · 44/74,874 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.00279% 45/1,613,822 alleles · ultra-rare exomes 14/1,461,772 · genomes 31/152,050 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0588%	1,702
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro454Arg
Coding: c.1361C>G
MANE Select: NM_138927
dbSNP: rs372024048
Type: single nucleotide variant
Location: chr21:33550592 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SON p.Pro454= Likely benign ★ same residue
SON p.Pro454Ala Likely benign ★ same residue
SON p.Arg1112Ter Pathogenic ★★ same condition
SON p.Arg1031Cys Uncertain significance ★★ ⚠ same condition
SON p.Arg1993Cys Uncertain significance ★★ ⚠ same condition
SON p.Gly47Asp Uncertain significance ★★ ⚠ same condition
SON p.Ser1437Cys Uncertain significance ★★ ⚠ same condition
SON p.Thr1156Lys 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/son-p-pro454arg (accessed [today's date]).

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