Is SON p.Met1024Val (c.3070A>G) pathogenic?

SON p.Met1024Val (c.3070A>G) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-15). AlphaMissense: ambiguous (0.3586); Very rare (popmax 0.00878%, sas); Associated with Inborn genetic diseases.

What condition is associated with SON p.Met1024Val (c.3070A>G)?

SON p.Met1024Val (c.3070A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SON p.Met1024Val (c.3070A>G) in the general population?

SON p.Met1024Val (c.3070A>G) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about SON p.Met1024Val (c.3070A>G)?

AlphaMissense predicts ambiguous (score 0.3586) — an in-silico prediction, not a clinical call.

SON p.Met1024Val

c.3070A>G · rs145573687 · VCV2168800

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3586	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -11.73	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 4.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 968 bp · p 9.6e-05 · regional, not allelic
Overall
CADD	28.1	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 0.00878% South Asian · 8/91,070 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00186% 30/1,613,950 alleles · very rare exomes 28/1,461,866 · genomes 2/152,084 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,384
African / African-American	0.00534%	18,720
Admixed American	0.005%	19,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00102%	98,332

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.Met1024Val
Coding: c.3070A>G
MANE Select: NM_138927
dbSNP: rs145573687
Type: single nucleotide variant
Location: chr21:33552301 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 1024: the '14 x 6 aa repeats of [ed]-r-s-m-m-s' region

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.Met1024Ile Uncertain significance ★ ⚠ 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
SON p.Ala1109Val Likely benign ★★ 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-met1024val (accessed [today's date]).

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