Is AMPH p.Arg256Ser (c.766C>A) pathogenic?

AMPH p.Arg256Ser (c.766C>A) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.9841); Ultra-rare (popmax 0.0167%, mid).

How common is AMPH p.Arg256Ser (c.766C>A) in the general population?

AMPH p.Arg256Ser (c.766C>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about AMPH p.Arg256Ser (c.766C>A)?

AlphaMissense predicts likely pathogenic (score 0.9841) — an in-silico prediction, not a clinical call.

AMPH p.Arg256Ser

c.766C>A · rs777511764 · VCV3117002

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9841	likely pathogenic
REVEL	0.36	indeterminate
SaProt	LLR -12.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.21	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.37 · regional, not allelic
Overall
CADD	26.8	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 0.0167% Middle Eastern · 1/5,990 alleles

Overall 6.2e-05% 1/1,613,470 alleles · ultra-rare exomes 1/1,461,194 · genomes 0/152,276 · joint denominator

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: AMPH
Protein: p.Arg256Ser
Coding: c.766C>A
MANE Select: NM_001635
dbSNP: rs777511764
Type: single nucleotide variant
Location: chr7:38463097 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 256: the 'disordered' region

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

Similar variants

AMPH c.1017+10T>C Likely benign ★★ same type
AMPH p.Thr586Met Likely benign ★★ same type
AMPH p.Ala10Thr Uncertain significance ★ ⚠ same type
AMPH p.Ala169Gly Uncertain significance ★ ⚠ same type
AMPH p.Ala239Ser Uncertain significance ★ ⚠ same type
AMPH p.Ala248Val Uncertain significance ★ ⚠ same type
AMPH p.Ala284Val Uncertain significance ★ ⚠ same type
AMPH p.Ala287Thr 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/amph-p-arg256ser (accessed [today's date]).

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