Is EGFLAM p.Pro740Thr (c.2218C>A) pathogenic?

EGFLAM p.Pro740Thr (c.2218C>A) is classified Uncertain significance in EGFLAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4042); Very rare (popmax 0.00271%, nfe).

How common is EGFLAM p.Pro740Thr (c.2218C>A) in the general population?

EGFLAM p.Pro740Thr (c.2218C>A) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about EGFLAM p.Pro740Thr (c.2218C>A)?

AlphaMissense predicts ambiguous (score 0.4042) — an in-silico prediction, not a clinical call.

EGFLAM p.Pro740Thr

c.2218C>A · VCV4247242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4042	ambiguous
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -8.94	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 205 kb · p 0.46 · regional, not allelic
Overall
CADD	25.2	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 0.00271% European (non-Finnish) · 32/1,179,992 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00217% 35/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,875
Admixed American	0.00167%	59,980
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,848

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: EGFLAM
Protein: p.Pro740Thr
Coding: c.2218C>A
MANE Select: NM_152403
Type: single nucleotide variant
Location: chr5:38435188 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.81 · 3 PDB
Residue 740: the laminin g-like 2 domain

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

Similar variants

EGFLAM p.Asn913= Benign ★★ same type
EGFLAM p.Trp229Arg Benign ★★ same type
EGFLAM c.2465-2611T>C Uncertain significance ★ ⚠ same type
EGFLAM p.Ala115Val Uncertain significance ★ ⚠ same type
EGFLAM p.Ala143Pro Uncertain significance ★ ⚠ same type
EGFLAM p.Ala314Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala45Thr Uncertain significance ★ ⚠ same type
EGFLAM p.Ala515Thr Uncertain significance ★ ⚠ 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/egflam-p-pro740thr (accessed [today's date]).

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