Is SON p.Ala1005Ser (c.3013G>T) pathogenic?

SON p.Ala1005Ser (c.3013G>T) is classified Benign/Likely benign in SON (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.4322); Ultra-rare (popmax 0.0157%, nfe); Associated with ZTTK syndrome.

What condition is associated with SON p.Ala1005Ser (c.3013G>T)?

SON p.Ala1005Ser (c.3013G>T) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Ala1005Ser (c.3013G>T) in the general population?

SON p.Ala1005Ser (c.3013G>T) is ultra-rare (popmax 0.0157%, nfe) (gnomAD).

What do computational predictors say about SON p.Ala1005Ser (c.3013G>T)?

AlphaMissense predicts ambiguous (score 0.4322) — an in-silico prediction, not a clinical call.

SON p.Ala1005Ser

c.3013G>T · rs142482063 · VCV1382322

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4322 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.4322	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -8.09	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 968 bp · p 9.6e-05 · regional, not allelic
Overall
CADD	29.4	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 0.0157% European (non-Finnish) · 185/1,180,026 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0126% 203/1,614,036 alleles · ultra-rare exomes 184/1,461,894 · genomes 19/152,142 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
European (non-Finnish)grpmax	0.0157%	6,379
Admixed American	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0096%	10,415

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1005Ser
Coding: c.3013G>T
MANE Select: NM_138927
dbSNP: rs142482063
Type: single nucleotide variant
Location: chr21:33552244 (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

ZTTK syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SON p.Ala1005Val Uncertain significance ★ ⚠ same residue
SON p.Ala1005= Likely benign ★ same residue
SON c.6321+1G>A Pathogenic ★★ same condition
SON p.Arg1081Ter Pathogenic ★★ same condition
SON p.Arg1112Ter Pathogenic ★★ same condition
SON p.Arg2008Ter Pathogenic ★★ same condition
SON p.Gln96Ter Pathogenic/Likely pathogenic ★★ same condition
SON c.6657+316G>A 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-ala1005ser (accessed [today's date]).

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