Is SON p.Leu449Phe (c.1347G>T) pathogenic?

SON p.Leu449Phe (c.1347G>T) is classified Uncertain significance in SON (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0946); Ultra-rare (popmax 0.0164%, mid); Associated with ZTTK syndrome.

What condition is associated with SON p.Leu449Phe (c.1347G>T)?

SON p.Leu449Phe (c.1347G>T) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Leu449Phe (c.1347G>T) in the general population?

SON p.Leu449Phe (c.1347G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SON p.Leu449Phe (c.1347G>T)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

SON p.Leu449Phe

c.1347G>T · rs1242440478 · VCV2584671

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -9.23	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 7.6	GERP 3.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	24.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,850 alleles · ultra-rare exomes 15/1,461,794 · genomes 2/152,056 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00127%	78,666

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.Leu449Phe
Coding: c.1347G>T
MANE Select: NM_138927
dbSNP: rs1242440478
Type: single nucleotide variant
Location: chr21:33550578 (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 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
SON p.Ala817Ser Uncertain significance ★★ ⚠ same condition
SON p.Ala847Pro 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-leu449phe (accessed [today's date]).

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