Is EGFR p.Pro631Ser (c.1891C>T) pathogenic?

EGFR p.Pro631Ser (c.1891C>T) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1023); Ultra-rare (popmax 0.045%, sas); Associated with EGFR-related lung cancer.

What condition is associated with EGFR p.Pro631Ser (c.1891C>T)?

EGFR p.Pro631Ser (c.1891C>T) is associated with EGFR-related lung cancer, hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Pro631Ser (c.1891C>T) in the general population?

EGFR p.Pro631Ser (c.1891C>T) is ultra-rare (popmax 0.045%, sas) (gnomAD).

What do computational predictors say about EGFR p.Pro631Ser (c.1891C>T)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

EGFR p.Pro631Ser

c.1891C>T · rs552265738 · VCV950603

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EGFR-related lung cancer

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 5,789 bp · p 0.00013 · regional, not allelic
Overall
CADD	23.4	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 0.045% South Asian · 41/91,086 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00266% 43/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.045%	2,222
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Pro631Ser
Coding: c.1891C>T
MANE Select: NM_005228
dbSNP: rs552265738
Type: single nucleotide variant
Location: chr7:55171185 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB
Residue 631: a β-strand; a disulfide bond

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

Disease context

Also linked: hereditary neoplastic syndrome

Similar variants

EGFR p.Pro631Arg Uncertain significance ★ ⚠ 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
EGFR c.1920-3C>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-pro631ser (accessed [today's date]).

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