Is EGFR p.Pro512Ser (c.1534C>T) pathogenic?

EGFR p.Pro512Ser (c.1534C>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0553); Very rare (popmax 0.0011%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Pro512Ser (c.1534C>T)?

EGFR p.Pro512Ser (c.1534C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Pro512Ser (c.1534C>T) in the general population?

EGFR p.Pro512Ser (c.1534C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Pro512Ser (c.1534C>T)?

AlphaMissense predicts likely benign (score 0.0553) — an in-silico prediction, not a clinical call.

EGFR p.Pro512Ser

c.1534C>T · rs587778248 · VCV134020

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0553 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0553	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -4.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.64	GERP -2.5
Regional constraint	o/e 0.85	unconstrained · MANE · 8,628 bp · p 0.0087 · regional, not allelic
Overall
CADD	0.092	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% European (non-Finnish) · 13/1,180,058 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,142 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: EGFR
Protein: p.Pro512Ser
Coding: c.1534C>T
MANE Select: NM_005228
dbSNP: rs587778248
Type: single nucleotide variant
Location: chr7:55161534 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 512: a disulfide bond

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGFR p.Pro512Leu Uncertain significance ★ ⚠ same residue
EGFR p.Pro512= Likely benign ★ same residue
EGFR c.1207+5G>A Uncertain significance ★★ same condition
EGFR c.1298+3A>G Uncertain significance ★★ same condition
EGFR c.1298+4A>G Uncertain significance ★★ same condition
EGFR c.1298+6T>C Uncertain significance ★★ same condition
EGFR c.1499-3C>T Uncertain significance ★★ same condition
EGFR c.1499-4G>T 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/egfr-p-pro512ser (accessed [today's date]).

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