Is DHFR p.Phe59= (c.177C>T) pathogenic?

DHFR p.Phe59= (c.177C>T) is classified Conflicting classifications of pathogenicity in DHFR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0333%, mid).

How common is DHFR p.Phe59= (c.177C>T) in the general population?

DHFR p.Phe59= (c.177C>T) is ultra-rare (popmax 0.0333%, mid) (gnomAD).

DHFR p.Phe59=

c.177C>T · rs1359361476 · VCV1546844

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, mid)

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 5.1	GERP 1.4, phastCons 1
Overall
CADD	9.338	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Middle Eastern · 2/6,004 alleles

Filtering AF 0.00587% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00062% 10/1,613,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0333%	3,002
African / African-American	0.008%	12,502
South Asian	0.0022%	45,492

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: DHFR
Protein: p.Phe59=
Coding: c.177C>T
MANE Select: NM_000791
dbSNP: rs1359361476
Type: single nucleotide variant
Location: chr5:80649454 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 96.32 · 89 PDB
Residue 59: the dhfr domain; an α-helix

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

Similar variants

MSH3 p.Ala59Pro Uncertain significance ★★ ⚠ same residue
MSH3 p.Ala59= Likely benign ★★ same residue
MSH3 p.Ala59Glu Uncertain significance ★ ⚠ same residue
MSH3 p.Ala59Gly Uncertain significance ★ ⚠ same residue
MSH3 p.Ala59Thr Uncertain significance ★ ⚠ same residue
MSH3 p.Ala59_Ala60insProProAlaAlaAlaAla Uncertain significance ★ same residue
MSH3 p.Ala59_Ala60insProProAlaProProAlaProProAla Uncertain significance ★ same residue
DHFR c.-476C>G 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/dhfr-p-phe59 (accessed [today's date]).

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