Is AGER p.Phe206Ser (c.617T>C) pathogenic?

AGER p.Phe206Ser (c.617T>C) is classified Uncertain significance in AGER (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.8552); Very rare (popmax 0.00441%, nfe).

How common is AGER p.Phe206Ser (c.617T>C) in the general population?

AGER p.Phe206Ser (c.617T>C) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about AGER p.Phe206Ser (c.617T>C)?

AlphaMissense predicts likely pathogenic (score 0.8552) — an in-silico prediction, not a clinical call.

AGER p.Phe206Ser

c.617T>C · VCV4023739

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8552 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8552	likely pathogenic · top 4% in AGER
REVEL	0.358	indeterminate
SaProt	LLR -14.66	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,076 bp · p 0.25 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00441% European (non-Finnish) · 52/1,179,510 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00335% 54/1,611,974 alleles · very rare exomes 50/1,459,682 · genomes 4/152,292 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,683
Remaining individualsnot grpmax-eligible	0.0032%	31,214

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: AGER
Protein: p.Phe206Ser
Coding: c.617T>C
MANE Select: NM_001136
Type: single nucleotide variant
Location: chr6:32182915 (GRCh38)
Gene constraint: LOEUF 1.068 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.74 · 33 PDB
Residue 206: a β-strand; the ig-like c2-type 1 domain

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

Similar variants

AGER p.Ala19Gly Uncertain significance ★ ⚠ same type
AGER p.Ala355Thr Uncertain significance ★ ⚠ same type
AGER p.Ala375Ser Uncertain significance ★ ⚠ same type
AGER p.Ala41Val Uncertain significance ★ ⚠ same type
AGER p.Ala6Val Uncertain significance ★ ⚠ same type
AGER p.Ala76Val Uncertain significance ★ ⚠ same type
AGER p.Arg116Leu Uncertain significance ★ ⚠ same type
AGER p.Arg178Ser 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/ager-p-phe206ser (accessed [today's date]).

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