Is EGFLAM p.Arg674His (c.2021G>A) pathogenic?

EGFLAM p.Arg674His (c.2021G>A) is classified Uncertain significance in EGFLAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.1939); Rare (popmax 0.249%, afr).

How common is EGFLAM p.Arg674His (c.2021G>A) in the general population?

EGFLAM p.Arg674His (c.2021G>A) is rare (popmax 0.249%, afr) (gnomAD).

What do computational predictors say about EGFLAM p.Arg674His (c.2021G>A)?

AlphaMissense predicts likely benign (score 0.1939) — an in-silico prediction, not a clinical call.

EGFLAM p.Arg674His

c.2021G>A · VCV4247236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1939 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.249%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1939	likely benign
REVEL	0.711	pathogenic-leaning
SaProt	LLR -10.09	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.81, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 205 kb · p 0.46 · regional, not allelic
Overall
CADD	32.0	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 0.249% African / African-American · 187/75,048 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.0154% 248/1,614,110 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.249%	401
Admixed American	0.055%	1,819
Middle Eastern	0.033%	3,028
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,228
Remaining individualsnot grpmax-eligible	0.0128%	7,814
South Asian	0.00659%	15,179
European (non-Finnish)	0.000424%	235,999

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.Arg674His
Coding: c.2021G>A
MANE Select: NM_152403
Type: single nucleotide variant
Location: chr5:38427219 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.81 · 3 PDB
Residue 674: 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-arg674his (accessed [today's date]).

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