Is SRC p.Glu492Lys (c.1474G>A) pathogenic?

SRC p.Glu492Lys (c.1474G>A) is classified Uncertain significance in SRC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.2611); Very rare (popmax 0.00573%, sas).

How common is SRC p.Glu492Lys (c.1474G>A) in the general population?

SRC p.Glu492Lys (c.1474G>A) is very rare (popmax 0.00573%, sas) (gnomAD).

What do computational predictors say about SRC p.Glu492Lys (c.1474G>A)?

AlphaMissense predicts likely benign (score 0.2611) — an in-silico prediction, not a clinical call.

SRC p.Glu492Lys

c.1474G>A · rs367543248 · VCV98534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00573%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2611	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	27.7	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 0.00573% South Asian · 5/87,204 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.000946% 15/1,586,168 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00573%	17,441
Admixed American	0.00533%	18,748
Remaining individualsnot grpmax-eligible	0.00163%	61,474
European (non-Finnish)	0.000514%	194,637

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.Glu492Lys
Coding: c.1474G>A
MANE Select: NM_198291
dbSNP: rs367543248
Type: single nucleotide variant
Location: chr20:37403242 (GRCh38)
Gene constraint: LOEUF 0.383 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 79 PDB
Residue 492: the protein kinase domain; an α-helix

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

Similar variants

SRC p.Glu527Lys Pathogenic/Likely pathogenic ★★ same type
SRC c.1117-180C>T Benign ★★ same type
SRC c.1117-9C>T Likely benign ★★ same type
SRC c.1271-55= Benign ★★ same type
SRC c.449+9C>T Benign/Likely benign ★★ same type
SRC c.553+8C>T Benign/Likely benign ★★ same type
SRC c.554-5C>T Benign ★★ same type
SRC p.Ala378= Benign/Likely benign ★★ 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/src-p-glu492lys (accessed [today's date]).

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