Is SON p.Ala737Val (c.2210C>T) pathogenic?

SON p.Ala737Val (c.2210C>T) is classified Benign in SON (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-08). AlphaMissense: likely pathogenic (0.7678); Ultra-rare (popmax 0.032%, afr).

How common is SON p.Ala737Val (c.2210C>T) in the general population?

SON p.Ala737Val (c.2210C>T) is ultra-rare (popmax 0.032%, afr) (gnomAD).

What do computational predictors say about SON p.Ala737Val (c.2210C>T)?

AlphaMissense predicts likely pathogenic (score 0.7678) — an in-silico prediction, not a clinical call.

SON p.Ala737Val

c.2210C>T · rs143709811 · VCV1433269

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7678	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -10.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 447 bp · p 0.4 · regional, not allelic
Overall
CADD	24.1	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 0.032% African / African-American · 24/75,006 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00297% 48/1,614,090 alleles · ultra-rare exomes 30/1,461,854 · genomes 18/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,125
Admixed American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.008%	12,501
South Asian	0.00549%	18,217
East Asian	0.00223%	44,886
European (non-Finnish)	0.000424%	235,993

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.Ala737Val
Coding: c.2210C>T
MANE Select: NM_138927
dbSNP: rs143709811
Type: single nucleotide variant
Location: chr21:33551441 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 737: the '17 x 10 aa tandem repeats of l-a-[st]-[nsg]-[ts]-mdsqm' region

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

Similar variants

SON p.Ala737Gly Uncertain significance ★ ⚠ same residue
SON p.Ala737= Likely 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
SON p.Arg2008Ter Pathogenic ★★ same type
SON p.Gln96Ter Pathogenic/Likely 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-ala737val (accessed [today's date]).

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