Is SRC p.Glu527Lys (c.1579G>A) pathogenic?

SRC p.Glu527Lys (c.1579G>A) is classified Pathogenic/Likely pathogenic in SRC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.9967); Very rare (popmax 8.49e-05%, nfe); Associated with SRC-related disorder.

What condition is associated with SRC p.Glu527Lys (c.1579G>A)?

SRC p.Glu527Lys (c.1579G>A) is associated with SRC-related disorder, thrombocytopenia, osteoporosis (ClinVar).

How common is SRC p.Glu527Lys (c.1579G>A) in the general population?

SRC p.Glu527Lys (c.1579G>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about SRC p.Glu527Lys (c.1579G>A)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

SRC p.Glu527Lys

c.1579G>A · rs879255268 · VCV225689

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

SRC-related disorder

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar
REVEL	0.363	indeterminate
SaProt	LLR -13.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 5,565 bp · p 1.1e-23 · regional, not allelic
Overall
CADD	33.0	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 8.49e-05% European (non-Finnish) · 1/1,177,410 alleles

Overall 6.88e-05% 1/1,454,178 alleles · very rare

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: SRC
Protein: p.Glu527Lys
Coding: c.1579G>A
MANE Select: NM_198291
dbSNP: rs879255268
Type: single nucleotide variant
Location: chr20:37403347 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 79 PDB
Residue 527: a UniProt-annotated variant site (in thc6; increased protein tyrosine kinase activity; increased autophosphorylation at y-419; causes defective megakaryopoiesis associated with increased overall tyrosine phosphorylation in megakaryocytes)

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

Disease context

SRC-related disorder

Also linked: thrombocytopenia osteoporosis primary myelofibrosis thrombocytopenia 6

Similar variants

SRC p.Gln529Glu Uncertain significance ★ ⚠ same condition
SRC p.Pro307Ser Uncertain significance ★ ⚠ same condition
SRC p.Thr357Ile Uncertain significance ★ ⚠ same condition
SRC c.450-8A>T Likely benign same condition
SRC p.Glu283= Likely benign same condition
SRC p.Phe175= Likely benign same condition
SRC p.Pro532= Likely benign same condition
SRC p.Ser212= Likely benign 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/src-p-glu527lys (accessed [today's date]).

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