Is LAMB3 p.Phe689Ser (c.2066T>C) pathogenic?

LAMB3 p.Phe689Ser (c.2066T>C) is classified Uncertain significance in LAMB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: ambiguous (0.5622); Rare (popmax 0.2%, afr); Associated with Inborn genetic diseases.

What condition is associated with LAMB3 p.Phe689Ser (c.2066T>C)?

LAMB3 p.Phe689Ser (c.2066T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LAMB3 p.Phe689Ser (c.2066T>C) in the general population?

LAMB3 p.Phe689Ser (c.2066T>C) is rare (popmax 0.2%, afr) (gnomAD).

What do computational predictors say about LAMB3 p.Phe689Ser (c.2066T>C)?

AlphaMissense predicts ambiguous (score 0.5622) — an in-silico prediction, not a clinical call.

LAMB3 p.Phe689Ser

c.2066T>C · VCV3537109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5622 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5622	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -5.84	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 36 kb · p 0.27 · regional, not allelic
Overall
CADD	24.4	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 0.2% African / African-American · 150/75,026 alleles

Filtering AF 0.174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.00997% 161/1,614,116 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.2%	500
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00167%	60,030

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: LAMB3
Protein: p.Phe689Ser
Coding: c.2066T>C
MANE Select: NM_000228
Type: single nucleotide variant
Location: chr1:209623911 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.55
Residue 689: the 'domain ii' region

Full LAMB3 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

LAMB3 p.Ala1071Thr Uncertain significance ★★ ⚠ same condition
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LAMB3 p.Ala330Thr Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala330Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala590Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala825Thr Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala832Val Uncertain significance ★★ ⚠ same condition
LAMB3 p.Ala855Gly 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/lamb3-p-phe689ser (accessed [today's date]).

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