Is SON p.Ala973Val (c.2918C>T) pathogenic?

SON p.Ala973Val (c.2918C>T) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.6181); Ultra-rare (popmax 0.0267%, nfe).

How common is SON p.Ala973Val (c.2918C>T) in the general population?

SON p.Ala973Val (c.2918C>T) is ultra-rare (popmax 0.0267%, nfe) (gnomAD).

What do computational predictors say about SON p.Ala973Val (c.2918C>T)?

AlphaMissense predicts likely pathogenic (score 0.6181) — an in-silico prediction, not a clinical call.

SON p.Ala973Val

c.2918C>T · rs146185666 · VCV1432630

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6181	likely pathogenic
REVEL	0.124	moderately benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 968 bp · p 9.6e-05 · regional, not allelic
Overall
CADD	25.9	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 0.0267% European (non-Finnish) · 315/1,180,000 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0233%

Overall 0.0201% 325/1,613,952 alleles · ultra-rare exomes 306/1,461,852 · genomes 19/152,100 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0267%	3,746
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00401%	24,959
South Asian	0.0011%	91,078

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.Ala973Val
Coding: c.2918C>T
MANE Select: NM_138927
dbSNP: rs146185666
Type: single nucleotide variant
Location: chr21:33552149 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 973: the '11 x 7 aa tandem repeats of [dr]-p-y-r-[li][ag][qhp]' region

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

Similar variants

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
SON c.6657+316G>A 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-ala973val (accessed [today's date]).

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