Is LYN p.Ser457Phe (c.1370C>T) pathogenic?

LYN p.Ser457Phe (c.1370C>T) is classified Uncertain significance in LYN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely benign (0.3048); Very rare (popmax 0.0011%, sas).

How common is LYN p.Ser457Phe (c.1370C>T) in the general population?

LYN p.Ser457Phe (c.1370C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LYN p.Ser457Phe (c.1370C>T)?

AlphaMissense predicts likely benign (score 0.3048) — an in-silico prediction, not a clinical call.

LYN p.Ser457Phe

c.1370C>T · rs1808768553 · VCV1461065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3048	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 58 kb · p 1.8e-23 · regional, not allelic
Overall
CADD	26.4	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 0.0011% South Asian · 1/91,084 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,850 alleles · very rare exomes 2/1,461,664 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	0.00017%	589,929

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: LYN
Protein: p.Ser457Phe
Coding: c.1370C>T
MANE Select: NM_002350
dbSNP: rs1808768553
Type: single nucleotide variant
Location: chr8:56009941 (GRCh38)
Gene constraint: LOEUF 0.282 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.44 · 6 PDB
Residue 457: the protein kinase domain; an α-helix

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

Similar variants

LYN p.Ser457Cys Uncertain significance ★ ⚠ same residue
LYN p.Ser457= Likely benign ★ same residue
LYN p.Ala150Thr Uncertain significance ★★ ⚠ same type
LYN p.Ala70Thr Uncertain significance ★★ ⚠ same type
LYN p.Arg360Trp Uncertain significance ★★ ⚠ same type
LYN p.Glu47Asp Uncertain significance ★★ ⚠ same type
LYN p.Ile227Val Uncertain significance ★★ ⚠ same type
LYN p.Ser333Asn 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/lyn-p-ser457phe (accessed [today's date]).

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