Is EGFR p.Pro644Arg (c.1931C>G) pathogenic?

EGFR p.Pro644Arg (c.1931C>G) is classified Uncertain significance in EGFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-26). AlphaMissense: ambiguous (0.4529); Very rare (popmax 0.00136%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Pro644Arg (c.1931C>G)?

EGFR p.Pro644Arg (c.1931C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Pro644Arg (c.1931C>G) in the general population?

EGFR p.Pro644Arg (c.1931C>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about EGFR p.Pro644Arg (c.1931C>G)?

AlphaMissense predicts ambiguous (score 0.4529) — an in-silico prediction, not a clinical call.

EGFR p.Pro644Arg

c.1931C>G · VCV3714093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4529	ambiguous
REVEL	0.598	indeterminate
SaProt	LLR -8.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 0.95
Regional constraint	o/e 0.77	unconstrained · MANE · 29 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.7	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 0.00136% European (non-Finnish) · 16/1,180,054 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,614,076 alleles · very rare exomes 17/1,461,862 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,753
African / African-American	0.00133%	74,926
South Asian	0.0011%	91,096

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.Pro644Arg
Coding: c.1931C>G
MANE Select: NM_005228
Type: single nucleotide variant
Location: chr7:55172994 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 644: a β-strand

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.Pro644Leu Uncertain significance ★★ same residue
EGFR p.Pro644Ser Uncertain significance ★ ⚠ same residue
EGFR p.Pro644Thr Uncertain significance ★ ⚠ same residue
EGFR p.Pro644= 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

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-pro644arg (accessed [today's date]).

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