Is FREM2 p.Val554Met (c.1660G>A) pathogenic?

FREM2 p.Val554Met (c.1660G>A) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.2257); No allele count reported in gnomAD v4.1 (AN 1,614,004); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Val554Met (c.1660G>A)?

FREM2 p.Val554Met (c.1660G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Val554Met (c.1660G>A) in the general population?

FREM2 p.Val554Met (c.1660G>A) is no allele count reported in gnomAD v4.1 (AN 1,614,004) (gnomAD).

What do computational predictors say about FREM2 p.Val554Met (c.1660G>A)?

AlphaMissense predicts likely benign (score 0.2257) — an in-silico prediction, not a clinical call.

FREM2 p.Val554Met

c.1660G>A · VCV3851638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2257 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,004)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2257	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 0.73, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	26.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,614,004). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FREM2
Protein: p.Val554Met
Coding: c.1660G>A
MANE Select: NM_207361
Type: single nucleotide variant
Location: chr13:38689004 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FREM2 p.Ala1029Val Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala565Gly Uncertain significance ★★ same condition
FREM2 p.Ala61Pro Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1166Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1523Cys Uncertain significance ★★ same condition
FREM2 p.Arg156Leu Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1765Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1765His 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/frem2-p-val554met (accessed [today's date]).

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