Is AMFR p.Arg15Ser (c.43C>A) pathogenic?

AMFR p.Arg15Ser (c.43C>A) is classified Uncertain significance in AMFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-26). AlphaMissense: ambiguous (0.3509); Ultra-rare (popmax 0.0102%, amr).

How common is AMFR p.Arg15Ser (c.43C>A) in the general population?

AMFR p.Arg15Ser (c.43C>A) is ultra-rare (popmax 0.0102%, amr) (gnomAD).

What do computational predictors say about AMFR p.Arg15Ser (c.43C>A)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

AMFR p.Arg15Ser

c.43C>A · VCV3860944

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.71	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 11	GERP 0.63, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 16 kb · p 0.83 · regional, not allelic
Overall
CADD	24.7	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 0.0102% Admixed American · 4/39,388 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.000353% 5/1,417,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0102%	9,847
Remaining individualsnot grpmax-eligible	0.00188%	53,290

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: AMFR
Protein: p.Arg15Ser
Coding: c.43C>A
MANE Select: NM_001144
Type: single nucleotide variant
Location: chr16:56425285 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 13 PDB

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

Similar variants

AMFR p.Arg307Cys Uncertain significance ★★ ⚠ same type
AMFR p.Arg389His Uncertain significance ★★ ⚠ same type
AMFR c.707+1G>A Likely pathogenic ★ same type
AMFR p.Cys364Ter Pathogenic ★ same type
AMFR p.Ala231Ser Uncertain significance ★ ⚠ same type
AMFR p.Ala324Val Uncertain significance ★ ⚠ same type
AMFR p.Ala385Thr Uncertain significance ★ ⚠ same type
AMFR p.Ala407Pro 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/amfr-p-arg15ser (accessed [today's date]).

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