Is EGFLAM p.Val894Ala (c.2681T>C) pathogenic?

EGFLAM p.Val894Ala (c.2681T>C) is classified Uncertain significance in EGFLAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.2217); Ultra-rare (popmax 0.0165%, mid).

How common is EGFLAM p.Val894Ala (c.2681T>C) in the general population?

EGFLAM p.Val894Ala (c.2681T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about EGFLAM p.Val894Ala (c.2681T>C)?

AlphaMissense predicts likely benign (score 0.2217) — an in-silico prediction, not a clinical call.

EGFLAM p.Val894Ala

c.2681T>C · VCV4663383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2217 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2217	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 205 kb · p 0.46 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V902A vs ClinVar V894A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000205% 3/1,461,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00167%	60,004
European (non-Finnish)	8.48e-05%	1,179,938

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.Val894Ala
Coding: c.2681T>C
MANE Select: NM_152403
Type: single nucleotide variant
Location: chr5:38451452 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.81 · 3 PDB
Residue 894: a β-strand; the laminin g-like 3 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-val894ala (accessed [today's date]).

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