Is SON p.Met861Val (c.2581A>G) pathogenic?

SON p.Met861Val (c.2581A>G) is classified Likely benign in SON (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2558); Rare (popmax 0.113%, amr).

How common is SON p.Met861Val (c.2581A>G) in the general population?

SON p.Met861Val (c.2581A>G) is rare (popmax 0.113%, amr) (gnomAD).

What do computational predictors say about SON p.Met861Val (c.2581A>G)?

AlphaMissense predicts likely benign (score 0.2558) — an in-silico prediction, not a clinical call.

SON p.Met861Val

c.2581A>G · rs142324795 · VCV741625

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2558 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2558	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; 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 0.82	unconstrained · MANE · 968 bp · p 9.6e-05 · regional, not allelic
Overall
CADD	23.5	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 0.113% Admixed American · 68/60,024 alleles

Filtering AF 0.0917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0838%

Overall 0.0124% 200/1,613,682 alleles · rare exomes 180/1,461,394 · genomes 20/152,288 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.113%	883
Middle Eastern	0.0704%	1,421
Finnishnot grpmax-eligible	0.0312%	3,202
South Asian	0.0165%	6,071
East Asian	0.0156%	6,413
African / African-American	0.012%	8,333
Remaining individualsnot grpmax-eligible	0.00961%	10,410
European (non-Finnish)	0.00593%	16,857
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Met861Val
Coding: c.2581A>G
MANE Select: NM_138927
dbSNP: rs142324795
Type: single nucleotide variant
Location: chr21:33551812 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 861: 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.Met861Leu Uncertain significance ★ 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-met861val (accessed [today's date]).

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