Is AMBN p.Phe183Ser (c.548T>C) pathogenic?

AMBN p.Phe183Ser (c.548T>C) is classified Uncertain significance in AMBN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). AlphaMissense: likely benign (0.3296); Very rare (popmax 0.00352%, amr).

How common is AMBN p.Phe183Ser (c.548T>C) in the general population?

AMBN p.Phe183Ser (c.548T>C) is very rare (popmax 0.00352%, amr) (gnomAD).

What do computational predictors say about AMBN p.Phe183Ser (c.548T>C)?

AlphaMissense predicts likely benign (score 0.3296) — an in-silico prediction, not a clinical call.

AMBN p.Phe183Ser

c.548T>C · rs1737546453 · VCV3114615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3296	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 14 kb · p 0.31 · regional, not allelic
Overall
CADD	19.45	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

Grpmax group 0.00352% Admixed American · 2/56,870 alleles

Filtering AF 0.000583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.00019% 3/1,579,706 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00352%	28,435
Remaining individualsnot grpmax-eligible	0.00164%	60,920

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: AMBN
Protein: p.Phe183Ser
Coding: c.548T>C
MANE Select: NM_016519
dbSNP: rs1737546453
Type: single nucleotide variant
Location: chr4:70602640 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.05
Residue 183: the 'disordered' region

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

Similar variants

AMBN p.Ser70Ter Uncertain significance ★★ same type
AMBN p.Gly268Arg Likely benign ★★ same type
AMBN p.His294Gln Benign/Likely benign ★★ same type
AMBN p.Leu354Pro Benign ★★ same type
AMBN p.Val378Ile Benign ★★ same type
AMBN c.295-2A>C Likely pathogenic ★ same type
AMBN c.15+1G>A Uncertain significance ★ same type
AMBN c.571-1G>C Conflicting classifications of pathogenicity ★ 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/ambn-p-phe183ser (accessed [today's date]).

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