Is SON p.Ala2188Val (c.6563C>T) pathogenic?

SON p.Ala2188Val (c.6563C>T) is classified Likely benign in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: ambiguous (0.5048); Very rare (popmax 0.00329%, sas).

How common is SON p.Ala2188Val (c.6563C>T) in the general population?

SON p.Ala2188Val (c.6563C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about SON p.Ala2188Val (c.6563C>T)?

AlphaMissense predicts ambiguous (score 0.5048) — an in-silico prediction, not a clinical call.

SON p.Ala2188Val

c.6563C>T · rs758559171 · VCV1609417

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5048	ambiguous
REVEL	0.236	benign-leaning
SaProt	LLR -6.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 4.4, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 12 kb · p 4.9e-19 · regional, not allelic
Overall
CADD	23.1	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 0.00329% South Asian · 3/91,082 alleles

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

Overall 0.00143% 23/1,613,674 alleles · very rare exomes 22/1,461,614 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
East Asian	0.00223%	44,866
European (non-Finnish)	0.00161%	62,096

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.Ala2188Val
Coding: c.6563C>T
MANE Select: NM_138927
dbSNP: rs758559171
Type: single nucleotide variant
Location: chr21:33559681 (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.Ala2188= 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
SON c.6657+160A>C 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/son-p-ala2188val (accessed [today's date]).

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