Is SON p.Pro1249Gln (c.3746C>A) pathogenic?

SON p.Pro1249Gln (c.3746C>A) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.135); Very rare (popmax 0.00161%, nfe).

How common is SON p.Pro1249Gln (c.3746C>A) in the general population?

SON p.Pro1249Gln (c.3746C>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about SON p.Pro1249Gln (c.3746C>A)?

AlphaMissense predicts likely benign (score 0.135) — an in-silico prediction, not a clinical call.

SON p.Pro1249Gln

c.3746C>A · rs767171313 · VCV1502966

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.135	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -8.62	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 3.9	GERP 3.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,223 bp · p 0.00022 · regional, not allelic
Overall
CADD	23.3	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 0.00161% European (non-Finnish) · 19/1,180,036 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,614,178 alleles · very rare exomes 20/1,461,858 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Pro1249Gln
Coding: c.3746C>A
MANE Select: NM_138927
dbSNP: rs767171313
Type: single nucleotide variant
Location: chr21:33552977 (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

Similar variants

SON p.Pro1249Ala Uncertain significance ★ ⚠ same residue
SON p.Pro1249Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
SON p.Pro1249Leu Uncertain significance ★ ⚠ same residue
SON p.Pro1249Ser Benign ★ same residue
SON c.6321+1G>A Pathogenic ★★ same type
SON p.Arg1081Ter Pathogenic ★★ same type
SON p.Arg1112Ter Pathogenic ★★ same type
SON p.Arg1825Ter Pathogenic ★★ 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/son-p-pro1249gln (accessed [today's date]).

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