Is DHPS p.Val66Ile (c.196G>A) pathogenic?

DHPS p.Val66Ile (c.196G>A) is classified Uncertain significance in DHPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0768); Very rare (popmax 0.00432%, nfe).

How common is DHPS p.Val66Ile (c.196G>A) in the general population?

DHPS p.Val66Ile (c.196G>A) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about DHPS p.Val66Ile (c.196G>A)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

DHPS p.Val66Ile

c.196G>A · rs775500314 · VCV2375217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -1.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.58, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 5,925 bp · p 0.58 · regional, not allelic
Overall
CADD	16.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00432% European (non-Finnish) · 51/1,180,062 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00328% 53/1,614,164 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,138
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,964

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: DHPS
Protein: p.Val66Ile
Coding: c.196G>A
MANE Select: NM_001930
dbSNP: rs775500314
Type: single nucleotide variant
Location: chr19:12681571 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.95 · 89 PDB
Residue 66: an α-helix

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

Similar variants

DHPS p.Glu71Lys Uncertain significance ★★ ⚠ same type
DHPS p.Gly162Arg Uncertain significance ★★ ⚠ same type
DHPS p.Met124Leu Uncertain significance ★★ ⚠ same type
DHPS c.784+8G>T Likely benign ★★ same type
DHPS p.Lys358= Likely benign ★★ same type
DHPS p.Thr88= Likely benign ★★ same type
DHPS c.785-1G>C Likely pathogenic ★ same type
DHPS p.Gln194Ter Likely pathogenic ★ 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/dhps-p-val66ile (accessed [today's date]).

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