Is AMDHD2 p.Leu186= (c.556C>T) pathogenic?

AMDHD2 p.Leu186= (c.556C>T) is classified Likely benign in AMDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). Rare (popmax 0.124%, nfe).

How common is AMDHD2 p.Leu186= (c.556C>T) in the general population?

AMDHD2 p.Leu186= (c.556C>T) is rare (popmax 0.124%, nfe) (gnomAD).

AMDHD2 p.Leu186=

c.556C>T · rs376877052 · VCV2646064

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.124%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.69, phastCons 1
Overall
CADD	7.281	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.124% European (non-Finnish) · 1,459/1,178,552 alleles

Filtering AF 0.118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.116%

Overall 0.0969% 1,548/1,596,964 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.124%	808
Remaining individualsnot grpmax-eligible	0.0692%	1,445
Admixed American	0.0336%	2,975
Finnishnot grpmax-eligible	0.0241%	4,147
African / African-American	0.0173%	5,769
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,498

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: AMDHD2
Protein: p.Leu186=
Coding: c.556C>T
MANE Select: NM_001330449
dbSNP: rs376877052
Type: single nucleotide variant
Location: chr16:2527913 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.49 · 2 PDB
Residue 186: a β-strand

Full AMDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATP6V0C p.Pro49Leu Likely pathogenic ★★ same type
ATP6V0C p.Ala95Thr Likely pathogenic ★ same type
AMDHD2 c.970+10C>T Uncertain significance ★ same type
AMDHD2 c.970+19T>G Uncertain significance ★ same type
AMDHD2 c.970+40C>T Uncertain significance ★ same type
AMDHD2 c.970+7G>A Uncertain significance ★ same type
AMDHD2 c.971-18G>A Uncertain significance ★ same type
AMDHD2 c.971-27C>G 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/amdhd2-p-leu186 (accessed [today's date]).

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