Is SON p.Val435Ala (c.1304T>C) pathogenic?

SON p.Val435Ala (c.1304T>C) is classified Uncertain significance in SON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-12). AlphaMissense: likely benign (0.2086); Very rare (popmax 0.00535%, afr).

How common is SON p.Val435Ala (c.1304T>C) in the general population?

SON p.Val435Ala (c.1304T>C) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about SON p.Val435Ala (c.1304T>C)?

AlphaMissense predicts likely benign (score 0.2086) — an in-silico prediction, not a clinical call.

SON p.Val435Ala

c.1304T>C · rs914453114 · VCV2174592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2086	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	17.41	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,794 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,584 alleles · very rare exomes 4/1,461,792 · genomes 1/151,792 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,699
European (non-Finnish)	8.48e-05%	1,179,869

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.Val435Ala
Coding: c.1304T>C
MANE Select: NM_138927
dbSNP: rs914453114
Type: single nucleotide variant
Location: chr21:33550535 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 435: the 'disordered' region

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

Similar variants

SON p.Val435Met 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-val435ala (accessed [today's date]).

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