Is AMPH p.Val209Phe (c.625G>T) pathogenic?

AMPH p.Val209Phe (c.625G>T) is classified Uncertain significance in AMPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9268); Ultra-rare (popmax 0.0115%, sas).

How common is AMPH p.Val209Phe (c.625G>T) in the general population?

AMPH p.Val209Phe (c.625G>T) is ultra-rare (popmax 0.0115%, sas) (gnomAD).

What do computational predictors say about AMPH p.Val209Phe (c.625G>T)?

AlphaMissense predicts likely pathogenic (score 0.9268) — an in-silico prediction, not a clinical call.

AMPH p.Val209Phe

c.625G>T · VCV4093162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9268 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9268	likely pathogenic
REVEL	0.296	indeterminate
SaProt	LLR -12.92	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 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 166 kb · p 1e-06 · 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 0.0115% South Asian · 10/86,984 alleles

Filtering AF 0.0062% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00472%

Overall 0.001% 16/1,593,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0115%	8,698
Admixed American	0.00185%	54,076
European (non-Finnish)	0.000426%	234,811

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.Val209Phe
Coding: c.625G>T
MANE Select: NM_001635
Type: single nucleotide variant
Location: chr7:38466214 (GRCh38)
Gene constraint: LOEUF 0.697 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.84 · 6 PDB
Residue 209: the bar domain; an α-helix

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

Similar variants

AMPH p.Val209Ile Uncertain significance ★ ⚠ same residue
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

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-val209phe (accessed [today's date]).

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